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Rol de la via de senalizacion notch durante el desarrollo de estructuras craneofaciales.

THE ROLE OF NOTCH SIGNALING PATHWAY IN THE DEVELOPMENT OF CRANIOFACIAL STRUCTURES

INTRODUCCION

El complejo craneofacial esta formado por un conjunto de estructuras que incluyen, a groso modo, el viscerocraneo (cara) y el neurocraneo. (1) El desarrollo craneofacial es quizas uno de los procesos mas complejos durante la embriogenesis, ya que requiere una amplia variedad de interacciones entre los diversos tejidos embrionarios. (2,3) Los tejidos que dan origen a las estructuras craneofaciales en vertebrados, son derivados de ectodermo, mesodermo, endodermo y, adicionalmente, de las celulas de la cresta neural craneal (CCNC). (3,4) Durante la embriogenesis, senales provenientes del ectodermo y el endodermo contribuyen reciprocamente para regular procesos celulares como proliferacion, supervivencia, migracion y diferenciacion del mesenquima facial, a traves de interacciones epitelio- mesenquima. (5,6) El mesenquima facial esta compuesto tanto por celulas de la cresta neural craneal (CCNC) como por celulas del mesodermo paraxial cefalico. (7)

El mesodermo paraxial cefalico da origen a la musculatura voluntaria facial y celulas endoteliales, mientras que las CCNC dan origen al tejido conectivo craneofacial, como dentina, pulpa dental, cartilagos faciales, huesos del viscerocraneo, y region anterior de la base craneal. (3,5,7) Varias vias de senalizacion han sido implicadas durante el desarrollo del complejo craneofacial, dentro de las mas estudiadas tenemos BMP (Bone Morphogenetic protein), SHH(Sonic Hedgehog), WNT (Wingless), TGF-beta (Transforming Growth Factor Beta), FGF (Fibroblast Growth Factor) y mas recientemente se ha vinculado la via de senalizacion NOTCH. (8-11) La via de senalizacion celular NOTCH esta implicada durante la etapa embrionaria y posnatal en varios procesos celulares, como proliferacion, diferenciacion, apoptosis, mantenimiento de celulas madre indiferenciadas y decision de destino celular. (12) Mutaciones inducidas en varios genescomponentes de la via de senalizacion NOTCH como Jagged2 y Hes1, en modelos animales como el raton, han mostrado alteraciones en el desarrollo de varias estructuras craneofaciales como paladar, dientes, maxilares, base y boveda craneal. (13-15)

Dentro de las alteraciones craneofaciales mas sobresalientes, se han reportado: paladar hendido, alteraciones morfologicas y deficiente formacion de matrizde dentina, agenesia de huesos frontales, disminucion del tamano de los maxilares y cierre prematuro de las fisuras craneales, generando un fenotipo de craneosinostosis, involucrandose en esta ultima alteracion la participacion del gen Twist (10,13-15) Adicionalmente, entre el 70 y el 80% de los pacientes con sindrome de Alagille, reportan mutaciones en el gen Jagged1, el cual codifica un ligando perteneciente a la via NOTCH. (16) Este sindrome se caracteriza por alteraciones multiorganicas y craneofaciales, que incluyen frente ancha, barbilla puntiaguda, punta de la nariz bulbosa, apariencia facial de triangulo invertido y craneosinostosis ocasional. (17-19) Este articulo se hizo con el objetivo de revisar el rol de varios genes componentes de la via de senalizacion NOTCH, como Notch1, Notch2, Jagged1, Jagged2 y Hes1, durante el desarrollo de estructuras craneofaciales como paladar, dientes, craneo y maxilares.

Generalidades de la via de senalizacion

NOTCH

La via de senalizacion canonica de NOTCH es un mecanismo de senalizacion celula-celula conservado evolutivamente, el cual participa en una variedad de procesos celulares como: especificacion de destino celular, proliferacion, apoptosis, adhesion, transformacion epitelio-mesenquimal, migracion, angiogenesis, mantenimiento de celulas madre yhomeostasis de tejidos adultos. (12,20,21) La via de senalizacion canonica de NOTCH esta integrada por diversos componentes, entre los cuales podemos citar: receptores NOTCH, ligandos (DSL), genes diana (genes de la familia bHLH, Hesy Hey) y otras proteinas reguladoras de la via descritas en la tabla 1.

En mamiferos, como humanos y ratones, se han descrito cuatro receptores NOTCH (Notch1, Notch2, Notch3 y Notch4), cinco ligandos (Jag1, Jag2, Deltal, Delta3 y Delta4) y varios genes diana, dentro de los mas estudiados se incluyen Hes1, Hes5 y Hey1. (23) El receptor de la via NOTCH es una proteina transmembranal que recibe senales de ligandos transmembranales que son expresados en celulas vecinas. (22)

El contacto directo entre el receptor y el ligando desencadena una serie de eventos proteoliticos a nivel del receptor NOTCH, provocando que el dominio intracelular del receptor se tras lo que al nucleo donde activa la transcripcion de los genes diana Hes y Hey (figura 1). (22) Las senales que son transducidas por estos receptores tienen un papel central en diversas etapas del desarrollo embrionario. (24) De manera significativa, tanto las deficiencias y anormales aumentos de senalizacion NOTCH se han asociado con anomalias de desarrollo y cancer. (18,25-28)

[FIGURA 1 OMITIR]

El contacto entre el ligando de una celula senalizadora (celula en la parte superior) y el receptor NOTCH de una celula vecina (celula inferior), genera una serie de eventos proteoliticos a nivel de los dominios extracelular e intracelular del receptor NOTCH, provocando que el dominio intracelular NOTCH (NICD), se trasloque al nucleo, activando la transcripcion de los genes de la familia bHLH, Hes y Hey, a traves de la interaccion con el factor de trascripcion CSL y el coactivador MAML.

Via NOTCH en el desarrollo del paladar secundario

El desarrollo del paladar secundarlo toma lugar alrededor del estadio E12-E15 en ratones, correspondiente al periodo comprendido entre la 8.a y la 12.a semana de gestacion en humanos. (27) Durante este periodo, los procesos palatinos que emergen de los bordes internos de las prominencias maxilares, crecen verticalmente a lado y lado de la lengua, posteriormente se elevan y se posicionan horizontalmente sobre el dorso de la lengua, para finalmente contactar uno con otro y fusionarse, dando lugar a una division entre la cavidad oral y la cavidad nasal. (28) Cada uno de estos pasos durante la palatogenesis son altamente regulados por varias vias de senalizacion, y un fallo durante el crecimiento, elevacion, contacto o fusion de los procesos palatinos, genera una fisura palatina. (27)

Durante el desarrollo normal del paladar, se ha detectado la expresion de varios genes componentes de la via de senalizacion NOTCH. (10) Los genes que codifican para los receptores Notch2 y Notch3, se expresan en el mesenquima lingual, procesos maxilares, mandibulares y palatinos desde E12.5 hasta E14.5. Contrario a este patron de expresion mesenquimal, Jag2y Notch1 son coexpresados predominantemente en el epitelio lingual, maxilar, palatino y epitelio lateral mandibular. (10) Ratones con mutaciones homocigotas Jag2-/-, exhiben paladar hendido acompanado de fusiones ectopicas entre la region dorsal de la lengua y los procesos palatinos. (13) El fenotipo de paladar hendido en estos mutantes es atribuido a estas fusiones ectopicas que no permiten una elevacion adecuada de los procesos palatinos y, por consiguiente, la genesis de la hendidura palatina. (10,13)

Fusiones patologicas entre el paladar y la lengua han sido descritas en humanos. (29,30) Sin embargo, los mecanismos celulares y moleculares involucrados en este proceso patologico, no estan totalmente claros. Casey, en el 2006, identifico en el modelo de raton altos niveles del receptor Notch1 activado durante el proceso de diferenciacion de las celulas del periderma lingual, maxilar, palatino y mandibular, desde E11.5 hasta E14.5. (10) Los ratones mutantes [Jag2.sup.sm/sm] homocigotos, ademas de mostrar paladar hendido y fusiones entre la lengua y los procesos palatinos, presentan fusiones aberrantes entre los procesos maxilares y mandibulares, acompanado de reduccion de los niveles activados de Notch1 durante la formacion del periderma oral, con desorganizacion y perdida de la morfologia plana de las celulas peridermicas que recubren el paladar y la lengua. (10)

Lo anterior sugiere a Jag2 como el ligando responsable de la activacion de Notch1 y de la diferenciacion del periderma oral. Por lo tanto, la senalizacion Jag2-Notch1 parece ser tempo-espacialmente regulada durante el desarrollo temprano del paladar, para prevenir prematuras adhesiones entre los procesos palatinos con el resto del epitelio oral en contacto, y asi facilitar la elevacion, contacto, adhesion y fusion de los procesos palatinos. (10) Adicionalmente, otros autores han mostrado que la via de senalizacion NOTCH, mediada por Jag2 junto a IRF6 (transcription factor interferon regulatory factor 6), funcionan como vias de senalizacion convergentes durante el proceso de diferenciacion del epitelio oral, durante el periodo de palatogenesis. (31)

Otro de los genes pertenecientes a la via de senalizacion NOTCH implicados en el desarrollo de estructuras craneofaciales como el paladar, es el gen Hes1. (15) Ratones con mutaciones homocigotas [Hes1.sup.-/-], presentan alteraciones durante el proceso de palatogenesis secundaria, caracterizado por un crecimiento deficiente y una prematura elevacion y reorientacion horizontal de las crestas palatinas, lo cual genera un paladar hendido, dado que el deficiente tamano de las crestas palatinas no permite que estas puedan contactar y fusionarse en la mayoria de los mutantes. (15) Adicionalmente, estos ratones mutantes exhiben defectos en el desarrollo de la base craneal relacionados con agenesia del hueso esfenoides. Los mecanismos celulares y moleculares especificos involucrados en el fenotipo de estos mutantes aun es desconocido. Sin embargo, los autores sugieren que una diferenciacion temprana de las celulas de la cresta neural craneal con una reducida proliferacion, pudo haber inducido la elevacion prematura y deficiente tamano de las crestas palatinas. (15)

Via de senalizacion NOTCH durante la odontogenesis: Jagged2 regula la diferenciacion y morfogenesis dental.

Ademas de la implicacion de la via NOTCH en el desarrollo de estructuras como paladar, varios componentes de esta via de senalizacion han sido identificados durante el desarrollo dental de ratones. Varios estudios han evidenciado que los componentes de la via de senalizacion NOTCH se expresan durante el desarrollo dental de ratones. La expresion de Notch1, Notch2, Notch3 (32), Dll1 (33), Jag1 (34) y Jag2 (35,36) prefiguran en el desarrollo dental en la subdivision de regiones ameloblasticas y no ameloblasticas, en las etapas iniciales del desarrollo dental (tabla 2). Esto se hace evidente durante la etapa de citodiferenciacion, en la que varios receptores NOTCH y varios de sus ligandos, muestran patrones de expresion complementarios: la expresion de Notch1 se limita al estrato intermedio, mientras que Dll1 y Jag2 estan expresados en la capa adyacente al epitelio dental interno (figura 2) (33,35,36)

Del mismo modo, en el mesenquima dental, Dll1 se expresa en odontoblastos en proceso de diferenciacion, mientras que los genes NOTCH se expresan predominantemente en la capa sub-odontoblastica. (34) Estos resultados sugieren que los receptores y ligandos de la via NOTCH participan en los procesos de diferenciacion celular durante el desarrollo dental. Recientes estudios han analizado la expresion, regulacion y funcion del gen Jag2 en desarrollo dental de ratones. (14) Estos estudios han mostrado que Jag2 se expresa en las celulas epiteliales, que daran lugar a la produccion de esmalte (ameloblastos) durantelas primeras etapas del desarrollo dental.

Asi mismo, en experimentos de recombinacion tisular, se evidencio que la expresion de Jag2en el epitelio esta regulada por senales derivadas del mesenquima. (14) Cultivos in vitro de explantes de epitelio dental muestran como la aplicacion local FGF estimula la expresion de Jag2, mientras que la aplicacion de BMP genera un efecto contrario. Lo anterior indica que durante el desarrollo dental, la expresion del gen Jag2 en el mesenqulma es controlado por FGF y BMP desde el mesenqulma. Ratones mutantes homocigotos Jag2 presentan una variedad de anomalias dentales. (14) En molares, la morfologia de la corona es deforme, con cuspides adicionales y en incisivos la citodiferenciacion de ameloblastos y la deposicion de matriz de esmalte son inhibidas.

[FIGURA 2 OMITIR]

Estos resultados demuestran que la via NOTCH, mediada por Jag2, es indispensable para una correcta odontogenesis. (14, 37, 38) Estudios recientes han permitido evidenciar una nueva funcion de la via NOTCH mediada por el receptor NOTCH1 y una de sus proteinas efectoras Hes1, en el desarrollo el asa cervical. Mediante el uso de un inhibidor de la via NOTCH, conocido como DAPT en modelos murinos in vitro e in vivo, se demostro que el bloqueo de la expresion del gen Hes1 dio lugar a un incremento en los niveles de apoptosis y una disminucion en la proliferacion de celulas madre del asa cervical. (39) Estos resultados indican que la via NOTCH a traves de Hes1 controla la supervivencia de las celulas madre epiteliales del asa cervical en desarrollo. (39)

Implicacion de la via NOTCH en el fenotipo craneofacial de pacientes con sindrome de Alagille y Hajdu Cheney

El sindrome de Alagille es un trastorno autosomlco dominante que afecta el sistema hepatico, cardiaco, esqueletico, renal, oftalmologico y el desarrollo facial. (17, 40) El sindrome de Alagille es causado predominantemente por una haploinsuficiencia del gen Jagged1. (16,19,41) Sin embargo, mutaciones en el gen Notch2 han sido identificadas en un subgrupo de pacientes con este sindrome.(18,42,43) El sindrome de Alagille se caracteriza por alteraciones craneofaciales que incluyen: frente ancha, barbilla puntiaguda, punta de la nariz bulbosa, hipoplasia del tercio medio facial que da la apariencia facial de triangulo invertido y craneosinostosis ocasional. (17-19,40,44) El clasico rasgo facial de V invertida es encontrado en un 95% de los pacientes que son diagnosticados, basado en el fenotipo de conducto intrabiliar hepatico. (40,45) Estos rasgos faciales sugieren que Jagged1 participa en la morfogenesis del tercio medio facial.

Varios modelos animales, como raton y zebrafish, han sido utilizados para modelar las caracteristicas del sindrome de Alagille, dentro de estas las craneofaciales. (46-48) El uso del modelo de raton ha permitido identificar cual es la funcion que desarrolla Jagged1 durante la morfogenesis facial. La deleccion de Jagged1 en celulas de la cresta neural craneal usando un raton Wnt1-cre; Jag1 Flox/ Floxpermitio recapitular el fenotipo de hipoplasia del tercio medio facial de pacientes con sindrome de Alagille. (49) La etiologia de la hipoplasia del tercio medio facial en estos ratones, fue una consecuencia de una proliferacion celular reducida de las CCNC en el tercio medio facial, aberrante vasculogenesis y deficiente produccion de matriz extracelular en los procesos palatinos, asociados con un crecimiento anormal de la region facial. (49) Especificamente, se evidencio tamano disminuido del maxilar superior y deficiente elongacion de los procesos palatinos.

Con respecto al desarrollo de la boveda craneal, Jagged1 ha sido implicado en el mantenimiento indiferenciado de celulas pre ontogenicas Inmaduras durante el desarrollo de las suturas craneales, garantizando asi un desarrollo armonioso entre el crecimiento del cerebro y el cierre de las suturas en modelos de raton. (50) Estos estudios han evidenciado que Jagged1 funciona como un gen blanco del factor de transcripcion TWIST1 para regular la expresion de genes como [beta]-catenina, Smad 1/3/8 y PrK1/2, implicados en la diferenciacion de osteoblastos de la boveda craneal. (50) De esta forma, Jagged1 mantiene indiferenciadas las celulas precursoras osteoblasticas y, por consiguiente, la permanencia de las suturas craneales. Mutaciones en Jagged1 resultan entonces en un cierre prematuro de las suturas coronales, generando asi un fenotipo de craneosinostosis como el observado de manera esporadica en el sindrome de Alagille. (44, 50)

Otro de los sindromes con alteraciones en el desarrollo de estructuras craneofaciales, es el sindrome de Hajdu-Cheney. (51,52) Este sindrome presenta una herencia autosomica dominante, aunque se pueden encontrar casos esporadicos. Los pacientes con este sindrome presentan una mutacion puntual en el exon 34 del gen Notch2, lo que genera un defecto en la sintesis del dominio PEST de la region intracelular de la proteina Notch2. (53) El dominio PEST esta involucrado en la ubiquitinacion y degradacion dela porcion intracelular del receptor NOTCH, por lo tanto, la ausencia de este dominio permite que la activacion de la via NOTCH no sea regulada adecuadamente. (22) El fenotipo craneofacial de los pacientes con sindrome de Hajdu-Cheney, incluye las siguientes caracteristicas: Dismorfismo facial, micrognatismo, deficiente cierre de suturas craneales y formacion de huesos wormianos. (51) Hasta la fecha no se ha evidenciado la funcion que cumple el gen Notch2 durante el desarrollo de las estructuras craneofaciales. Por lo tanto, es necesario que, mediante el uso de modelos animales, se investiguen los mecanismos celulares y moleculares alterados durante el desarrollo de las estructuras craneofaciales afectadas en este sindrome.

CONCLUSIONES

Los estudios actuales sobre alteraciones en genes componentes de la via NOTCH y su implicacion en el desarrollo de estructuras craneofaciales, como paladar, boveda craneal, base craneal y dientes, se limita a un numero restringido de genes que incluyen Jagged2, Jagged1, Notch1, Notch2 y Hes1. Sin embargo, los mecanismos celulares y moleculares implicados en cada alteracion del desarrollo resultante de la perdida de funcion de cada uno de estos genes, aun no es clara. Por lo que es necesario que, mediante el uso de modelos animales como raton u otros modelos que incluyen Zebrafish y pollo, se investigue la expresion de cada uno de los genes componentes de la via NOTCH en cada etapa del desarrollo y, por medio de estudios de perdida y ganancia de funcion genica, se establezca la funcion que desarrolla cada gen, tanto en etapas tempranas como tardias del desarrollo craneofacial.

Por otro lado, ademas de la necesidad de continuar ahondando en los aspectos celulares y moleculares de la via NOTCH en el desarrollo craneofacial, se hace necesario hacerestudios geneticos en poblaciones afectadas con defectos craneofaciales, como paladar hendido y defectos de asimetria facial, en donde se investigue la presencia de mutaciones en varios de los genes de la via NOTCH que han sido relacionados con estos defectos. Teniendo en cuenta los vacios aun existentes referentes a la funcion de la via NOTCH en el desarrollo craneofacial, es posible plantear los siguientes interrogantes que nos permitan orientar un proceso investigativo: ?Cual es la prevalencia de mutaciones en el gen Hes1 y Jagged2 en pacientes con paladar hendido? ?Ademas de los pacientes con Alagille, en que otros pacientes con asimetria facial se pueden identificar mutaciones en genes componentes de la via NOTCH, ademas de Jagged1 y Notch2?

RECIBIDO: ENERO 22/2012-ACEPTADO: NOVIEMBRE 19/2013

BELFRAN ALCIDES CARBONELL MEDINA [1]

[1] Odontologo, especialista en docencia universitaria, candidato a magister en Odontologia, Instituto de Genetica, Universidad Nacional de Colombia.

CORRESPONDENCIA

Belfran Alcides Carbonell

Universidad Nacional de Colombia

Carrera 34 No. 25C-12

Bogota D. C., Colombia

Correo electronico: bacarbonellm@unal.edu.co
Tabla 1. Componentes de la via NOTCH canonica por especies (12, 22)

Components      Aves                            Mamiferos

                Notch1                          Notch1
Receptores                                      Notch2
                Notch2                          Notch3
                                                Notch4
                Serrate1 (Jagged1)              Jagged1
                Serrate2 (Jagged2)              Jagged2
Ligandos        Delta1                          Delta1
                Delta4                          Delta3
                                                Delta4
                Hairy1 (Hes1)                   Hes1 - 7
                Hairy2 (Hes2)
                Hairy5 (Hes)
Genes blanco    Hairy6 (Hes6)
                Hey1                            Hey1
                Hey2                            Hey2
                HeyL                            HeyL
Proteinas       Lunatic, manic and              Lunatic, manic and
  reguladoras     radical fringe                  radical fringe

Components      Drosophila M.        C. Elegans

                                     Lin-12
Receptores      NOTCH
                                     GLP-1

                Serrate              APX-1
                Delta                LAG-1
Ligandos                             ARG-1
                                     DSL-1

Genes blanco    E (psl) bHLH         REF-1

Proteinas       Fringe               No identificados
  reguladoras

Tabla 2. Expresion y funcion de genes componentes de la via NOTCH
durante el desarrollo dental

Etapas del desarrollo    Patrones de expresion de componentes de
  dental en ratones      la via NOTCH en odontogenesis

                         Expresion de Notch1, Notch2 y Notch3
                           en lamina dental (34)
Lamina dental (E11)      Jag2 en epitelio dental (14)
                         Jag1 en epitelio dental (36)
                         Delta1 en lamina dental (35)

                         Expresion de Notch1, Notch2 y Notch3 en todo
                           el epitelio dental (34)
                         Jag2 en epitelio dental interno y externo (14)

Brote (E12,5-E13,5)      Jag1 en epitelio dental y mesenquima, no se
                           observa expresion en epitelio dental
                           adyacente al mesenquima. (36) Ademas,
                           Delta1 en epitelio dental (35)
                         Hes1 en mesenquima condensado y epitelio
                           que dara lugar al reticulo estrellado

                         Notch1 en estrato intermedio y Notch2 en
                           reticulo estrellado (34)

Casquete (E14,5-E15,5)   Jag2 en epitelio dental interno (14) y Jag1 en
                           organo del esmalte (36)

                         Notch1 en organo del esmalte y asa
                           cervical (34)
                         Notch2 y Notch3 en organo del esmalte
                           y papila dental, adicionalmente Notch2
                           en asa cervical (34)

Campana (E16,5-E18,5)    Jag2 en epitelio dental interno (14) Jag1 en
                           estrato intermedio, reticulo estrellado,
                          foliculo dental y papila dental (36) Delta1
                           en organo del esmalte, epitelio dental
                           interno, reticulo estrellado y estrato
                           intermedio. Ademas, se observa su
                           presencia en mesenquima que dara lugar
                           a pre-odon-toblastos y odontoblastos (35)

Etapas del desarrollo    Funciones reportadas
  dental en ratones      o relacionadas

Lamina dental (E11)

Brote (E12,5-E13,5)

                         Jag2 aparentemente regula los
                         niveles de apoptosis mediados por
Casquete (E14,5-E15,5)   el nodo del esmalte y
                         la morfogenesis dental (14)

Campana (E16,5-E18,5)    Jag2 esta involucrado en la diferenciacion
                         de odontoblastos, amelo-blastos y
                         la subsecuente deposicion de matriz
                         de esmalte y dentina (14)


INTRODUCTION

The craniofacial complex is formed by aset of structures including, roughly, the viscerocranium (face) and the neurocranium. (1) Craniofacial development is perhaps one of the most complex processes during embryogenesis since it requires a wide variety of interactions among different embryonic tissues. (2,3) The tissues that produce craniofacial structures in vertebrates originate from ectoderm, mesoderm, endoderm, and cranial neural crest cells (CrnNC). (3, 4) During embryogenesis, signals from the ectoderm and the endoderm reciprocally contribute to regulate cell processes such as proliferation, survival, migration, and differentiation of facial mesenchyme, through epithelial-mesenchymal interactions. (5,6) The facial mesenchyme contains cranial neural crest cells (CrnNC) as well as cells of the cephalic paraxial mesoderm. (7)

The cephalic paraxial mesoderm produces voluntary facial muscle and endothelial cells, whereas CrnNC produce craniofacial connective tissue, such as dentin, dental pulp, facial cartilage, viscerocranium bones, and the anterior region of the skull base. (3,5,7) Several signaling pathways have been associated to the development of the craniofacial complex, some of the most studied are BMP (Bone Morphogenetic Protein), SHH (Sonic Hedgehog), WNT (Wingless), TGF-beta (Transforming Growth Factor Beta), FGF (Fibroblast Growth Factor), and the NOTCH signaling pathway has been recently associated to it. (8-11) The NOTCH signaling pathway is involved in the embryonic and postnatal stages in several cell processes such as proliferation, differentiation, apoptosis, maintenance of undifferentiated stem cells, and cell fate differentiation. (12) Mutations induced in several genes of the NOTCH signaling pathway such as Jagged2 and Hes1 in animal models like mice have shown alterations in the development of various craniofacial structures including palate, teeth, jaws, cranial base, and cranial vault. (13-15)

The most commonly reported craniofacial alterations include cleft palate, morphological alterations and poor formation of dentin matrix, frontal bone agenesis, decreased maxillaries size, and premature closure of cranial fissures, generating a craniosynostosis phenotype with the participation of the Twist1 gene. (10,13-15) In addition, 70 to 80% of Alagille Syndrome patients report mutations in the Jagged1 gene, which encodes a ligand belonging to the NOTCH pathway. (16) This syndrome is characterized by multi-organic and craniofacial alterations such as wide forehead, pointed chin, bulbous nose tip, inverted triangle facial appearance, and occasional craniosynostosis. (17-19) The objective of this article was to review the role of NOTCH signaling pathway components, such as Notch1, Notch2, Jagged1, Jagged2, and Hes1, in the development of craniofacial structures like palate, teeth, skull, and maxillaries.

An overview of the NOTCH signaling pathway

Canonical NOTCH signaling pathway is an evolutionarily conserved mechanism of cell-cell signaling, which participates in a variety of cell processes suchascellfate specification, proliferation, apoptosis, adhesion, epithelial-mesenchymal transformation, migration, angiogenesis, stem cells maintenance, and homeostasis of adult tissues. (12, 20, 21) Canonical NOTCH signaling pathway contains several components, including NOTCH receptors, ligands (DSL), target genes (genes of the bHLH, Hes and Hey family), and other regulatory proteins of this pathway as described in table 1.

In mammals, like humans and mice, four NOTCH receptors (Notch1, Notch2, Notch3, and Notch4), five ligands (Jag1, Jag2, Delta1, Delta3, and Delta4) and several target genes have been described; some of the most studied are Hes1, Hes5, and Hey1. (23) The NOTCH pathway receptor is a transmembrane protein that receives signals of transmembrane ligands which are expressed in neighboring cells. (22)

Direct contact of receptor and ligand triggers a series of proteolytic events at the level of the NOTCH receptor, causing the receptor's intracellular domain to translocate to the nucleus where it activates transcription of target genes Hes and Hey (figure 1). (22) The signals transduced by these receptors play a pivotal role in various stages of embryonic development. (24) Deficiencies and abnormal growth of NOTCH signaling have been significantly associated with developmental anomalies and cancer. (18,25-28)

Contact between the ligand of a signaling cell (at the top) and the NOTCH receptor of a neighboring cell (at the bottom) produces a series of proteolytic events at the extracellular and intracellular domains of the NOTCH receptor, causing the NOTCH intracellular domain (NICD) to translocate to the nucleus, activating the transcription of genes of the bHLH, Hes and Hey family through interaction with CSL transcription factor and the MAML co-activator.

The NOTCH pathway in the development of secondary palate

The development of secondary palate takes place around stage E12-E15 in mice, corresponding to the period between the 8th and 12th week of gestation in humans. (27) During this period, the palatal processes generated at the internal edges of the maxillary prominences grow vertically on both sides of the tongue, then they elevate and position horizontally on the dorsum of tongue, to finally contact each another and merge, producing a split between the oral cavity and the nasal cavity. (28) Each of these palatogenesis steps are highly regulated by several signaling pathways, and any failure during growth, lifting, contact or fusion of the palatal processes produces cleft palate. (27)

The expression of several NOTCH signaling pathway genes has been detected during normal palate development. (10) Genes that encode for Notch2 and Notch3 receptors are expressed in the lingual mesenchyme and in mandibular, maxillary and palatal processes from E12.5 to E14.5. Contrary to this pattern of mesenchymal expression, Jag2 and Notch1 are co-expressed mainly in the lingual, maxillary and palatine epithelium and in the mandibular lateral epithelium. (10) Homozygous mice with Jag2-/- mutations show cleft palate accompanied by ectopic fusions between the dorsal region of the tongue and the palatal processes.13 The cleft palate phenotype in these mutants is attributed to such ectopic fusions, which inhibit proper elevation of the palatal processes and therefore generate cleft palate. (10,13)

Pathological palate-tongue fusions have been described in humans. (29,30) However, the cellular and molecular mechanisms involved in this pathology are not totally clear. In 2006, Casey identified in a mouse high levels of the Notch1 receptor activated during the differentiation process of cells of the lingual, palatal, maxillary and mandibular periderm, from E11.5 to E14.5. (10) Mutant [Jag2.sup.sm/sm] homozygous mice, in addition to cleft palate and palate-tongue fusions, show aberrant fusions between the maxillary and mandibular processes accompanied by reduction of Notch1 activated levels during the formation of oral periderm, with disorganization and loss of the flat morphology of the periderm cells that cover the palate and tongue. (10)

This suggests that Jag2 is the ligand responsible for activation of Notch1 and oral periderm differentiation. Therefore the Jag2-Notch1 signaling appears to be temporally and spatially regulated during early palate development, to prevent premature adhesions between palatal processes and the rest of the oral epithelium in contact, and thus facilitate lifting, contact, adhesion and fusion of palatal processes. (10) In addition, other authors have shown that NOTCH signaling pathway, mediated by Jag2 and IRF6 (transcription interferon regulatory factor 6) function as signaling pathways converging during the process of oral epithelium differentiation during palatogenesis. (31)

Another NOTCH signaling pathway gene involved in the development ofcraniofacial structures like palate is gene Hes1. (15) Mice with homozygous mutations [Hes1.sup.-/-] show alterations during secondary palatogenesis, characterized by poor growth, premature lifting, and horizontal reorientation of palatal ridges, which generates cleft palate since the small size of palatal ridges thwarts their contacting and merging in most mutants. (15) In addition, these mutant mice show defects in cranial base development associated with agenesis of the sphenoid bone. The specific cellular and molecular mechanisms involved in these mutants' phenotype are still unknown. However, the authors suggest that early differentiation of cranial neural crest cells with reduced proliferation may have induced premature elevation and inadequate size of the palatal ridges. (15)

NOTCH signaling pathway during odontogenesis: Jagged2 regulates tooth morphogenesis and differentiation

In addition to NOTCH pathway participation in the development of structures like palate, various components of this signaling pathway have been identified during tooth development in mice. Several studies have shown that components of the NOTCH signaling pathway are expressed during tooth development in mice. The expression of Notch1, Notch2, Notch3 (32), Dlll (33), Jag1 (34) and Jag2 (35,36) prefigure ameloblastic and non-ameloblastic region subdivision in the initial stages of tooth development (table 2). This is evident during the cytodifferentiation stage, in which several NOTCH receptors and some of their ligands show complementary expression patterns: Notch1 expression is limited to the intermediate layer, while Dll1 and Jag2 are expressed in the layer adjacent to the inner dental epithelium (figure 2). (33,35,36)

Similarly, in the dental mesenchyme, Dll1 is expressed in odontoblasts in process of differentiation, while NOTCH genes are expressed in the sub-odontoblastic layer mainly. (34) These findings suggest that receptors and ligands of the NOTCH pathway participate in the processes of cellular differentiation during tooth development. Recent studies have examined the expression, regulation, and function of Jag2 gen in tooth development in mice. (14) These studies have shown that Jag2 is expressed in epithelial cells, enabling enamel production (ameloblasts) during the early stages of tooth development.

Likewise, tissue recombination experiments have shown that Jag2 expression in the epithelium is regulated by signals from the mesenchyme. (14) In vitro cultures of dental epithelium explants show that local application of FGF stimulates Jag2 expression, while the application of BMP produces the opposite effect. This suggests that during tooth development, the Jag2 gene expression is controlled by FGF in mesenchyme and by BMP from mesenchyme. Homozygous Jag2 mutant mice show a variety of dental anomalies. (14) Their molars' crown morphology is deformed, with additional cusps, and their incisors ameloblast cytodifferentiation is inhibited as well as enamel matrix deposition.

These results demonstrate that the NOTCH pathway, mediated by Jag2, is essential for correct odontogenesis. (14, 37, 38) Recent studies have shown a new function of the NOTCH pathway mediated by the Notch1 receptor and one of its Hes1 effector proteins in the development of cervical loop. Using a NOTCH pathway inhibitor known as DAPT on in vitro and in vivo mouse models demonstrated that blocking the Hes1 gene expression resulted in an increase in apoptosis levels and a decrease in proliferation of stem cells from the cervical loop. (39) These findings suggest that, by means of Hes1, the NOTCH pathway controls survival of epithelial stem cells of the developing cervical loop. (39)

Involvement of the NOTCH pathway in the craniofacial phenotype of patients with Alagille Syndrome and Hajdu-Cheney Syndrome

Alagille Syndrome is an autosomal dominant disorder that affects the hepatic, cardiac, skeletal, kidney, and eye systems as well as facial development. (17, 40) Alagille Syndrome is caused by haploinsufficiency of gen Jagged1 mainly. (16,19,41) However, gene Notch2 mutations have been identified in a subgroup of patients with this syndrome. (18,42,43) Alagille Syndrome is characterized by craniofacial abnormalities including wide forehead, pointed chin, bulbous nose tip, and midfacial third hypoplasia, producing an inverted triangle facial appearance of occasional craniosynostosis. (17-19,40,44) The typical inverted V face feature is found in 95% of diagnosed patients, based on the intrabiliary hepatic duct phenotype. (40,45) These facial features suggest that Jagged1 is involved in midface morphogenesis.

Several animals like zebrafish and mice have been used to model Alagille Syndrome characteristics, including the craniofacial ones. (46-48) Mice models have allowed identifying the role of Jagged1 during facial morphogenesis. Deletion of Jagged1 in cranial neural crest cells using a Wnt1cre; Jag1 Flox/Flox mouse allowed recapitulating the midface hypoplasia phenotype in Alagille Syndrome patients. (49) The etiology of midface hypoplasia in these mice was a consequence of a reduced proliferation of CrnNC in the midface, aberrant vasculogenesis, and poor production of extracellular matrix in palatal processes, associated with abnormal growth in the facial area. (49) Decreased maxilla size and poor elongation of palatal processes were also evident.

Regarding cranial vault development, Jagged1 has been involved in the undifferentiated maintenance of immature pre-ontogenic cells during development of cranial sutures, ensuring a harmonious development of brain growth and sutures closing in mouse models. (50) These studies have shown that Jagged1 works as a target gene of the TWIST1 transcription factor to regulate the expression of genes such as [beta]-catenin, Smad 1/3/8 and PrK1/2, involved in cranial vault osteoblast differentiation. (50) Hence Jagged1 maintains osteoblastic precursor cells undifferentiated and therefore it keeps cranial sutures. Then, Jagged1 mutations result in premature closure of coronal sutures, generating a craniosynostosis phenotype, as sporadically observed in Alagille Syndrome. (44, 50)

Another syndrome with alterations in craniofacial structures development is the Hajdu-Cheney. (51, 52) This syndrome has autosomal dominant inheritance, although sporadic cases can also be found. Patients with this syndrome have a point mutation in exon 34 of gene Notch2, which produces a defect in the PEST domain synthesis of the intracellular region of protein Notch2. (53) The PEST domain is involved in the ubiquitination and degradation of the NOTCH receptor's intracellular portion; therefore, absence of this domain impedes the proper regulation of NOTCH pathway activation. (22) The craniofacial phenotype of Hajdu-Cheney syndrome patients includes the following features: facial dimorphism, micrognathism, poor closure of cranial sutures, and wormian bones formation. (51) The role of Notch2 gene during craniofacial structures development has not been established to date. Therefore, it is necessary to study animal models to analyze the cellular and molecular mechanisms that are altered during development of the craniofacial structures affected in this syndrome.

CONCLUSIONS

Current studies on NOTCH pathway's genes alterations and their involvement in craniofacial structures development, such as palate, cranial vault, cranial base, and teeth, is limited to a restricted number of genes, including Jagged2, Jagged1, Notch1, Notch2, and Hes1. However, the cellular and molecular mechanisms involved in each development alteration as a result of function loss in each of these genes are not yet clear. It is therefore necessary to use animal models such as mice, chicken and zebrafish to analyze the expression of each NOTCH pathway gene in every stage of development and, through studies of loss and gain of gene function, to establish the function of each gene in early and late stages of craniofacial development.

On the other hand, in addition to further research on the cellular and molecular aspects of NOTCH pathway in craniofacial development, it is necessary to perform genetic studies on populations affected by craniofacial defects such as cleft palate and facial asymmetry, in order to study the presence of mutations in several NOTCH pathway genes that have been associated with these defects. Taking into account the existing gaps concerning the function of NOTCH pathway in craniofacial development, it is possible to raise the following questions in order to direct new research: what is the prevalence of genes Hes1 and Jagged2 mutations in cleft palate patients? Apart from Alagille patients, in what other patients with facial asymmetry can NOTCH pathway gene mutations be identified, besides Jagged1 and Notch2?

SUBMITTED: JANUARY 22/2012-ACCEPTED: NOVEMBER 19/2013

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BELFRAN ALCIDES CARBONELL MEDINA [1]

[1] Dentist, higher education specialist, magister in Dentistry, Instituto de Genetica, Universidad Nacional de Colombia.

CORRESPONDING AUTHOR

Belfran Alcides Carbonell

Universidad Nacional de Colombia

Carrera 34 No. 25C-12

Bogota D. C., Colombia

Email address: bacarbonellm@unal.edu.co
Table 1. Components of the canonical Notch signaling pathway
per species(12, 22)

Components     Birds                Mammals              Drosophila M.

               Notch1               Notch1
Receptors                           Notch2               NOTCH
               Notch2               Notch3
                                    Notch4
               Serrate1 (Jagged1)   Jagged1              Serrate
               Serrate2 (Jagged2)   Jagged2              Delta
Ligands        Delta1               Delta1
               Delta4               Delta3
                                    Delta4
               Hairy1 (Hes1)        Hes1 - 7
               Hairy2 (Hes2)
               Hairy5 (Hes)
Target genes   Hairy6 (Hes6)                             E (psl) bHLH
               Hey1                 Hey1
               Hey2                 Hey2
               HeyL                 HeyL
Regulatory     Lunatic, manic and   Lunatic, manic and   Fringe
  proteins       radical fringe       radical fringe

Components     C. Elegans

               Lin-12
Receptors
               GLP-1

               APX-1
               LAG-1
Ligands        ARG-1
               DSL-1

Target genes   REF-1

Regulatory     Unidentified
  proteins

Table 2. Expression and function of NOTCH
path-way component genes during tooth development

Stages of tooth         Patterns of expression of NOTCH pathway
  development in mice     components during odontogenesis

                        Expression of Notch1, Notch2 and Notch3
                          in dental lamina (34)
Dental lamina (E11)     Jag2 in dental epithelium (14)
                        Jag1 in dental epithelium (36)
                        Delta1 in dental lamina (35)
                        Expression of Notch1, Notch2 and Notch3
                          in entire dental epithelium (34)

                        Jag2 in internal and external
                          dental epithelium (14)
Bud (E12, E13-5,5)      Jag1 in dental epithelium and mesenchyme,
                          there is no expression in dental
                          epithelium adjacent to mesenchyme. (36)
                          Also, Delta1 in dental epithelium (35)
                        Hes1 in condensed mesenchyme and
                          epithelium which will result in
                          stellate reticulum

Cap (E14, E15-5,5)      Notch1 in intermediate layer and Notch2
                          in stellate reticulum (34)
                        Jag2 in internal dental epithelium (14) and
                          Jag1 in enamel organ (36)

                        Notch1 in enamel organ and cervical loop (34)
                        Notch2 and Notch3 in enamel organ and dental
                          papilla; also, Notch2 in cervical loop (34)
Bell (E16,5-E18,5)      Jag2 in internal dental epithelium (14) Jag1
                          in intermediate layer, stellate reticulum,
                          dental follicle and dental papilla (36)
                          Delta1 in enamel organ, inner dental
                          epithelium, stellate reticulum and
                          intermediate layer. Also, its  presence
                          in mesenchyme will result in pre-
                          odontoblasts and odontoblasts (35)

Stages of tooth         Reported or related functions
  development in mice

Dental lamina (E11)

Bud (E12, E13-5,5)

Cap (E14, E15-5,5)      Jag2 apparently regulates apoptosis
                          levels mediated by enamel node
                          and tooth morphogenesis (14)

Bell (E16,5-E18,5)      Jag2 is involved in odontoblasts
                          and ameloblasts differentiation
                          and in the subsequent deposit of
                          matrix of enamel and dentin (14)
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