RESUMEN
Coordination of craniofacial development involves an complex, intricate, genetically controlled and tightly regulated spatiotemporal series of reciprocal inductive and responsive interactions among the embryonic cephalic epithelia (both endodermal and ectodermal) and the cephalic mesenchyme - particularly the cranial neural crest (CNC). The coordinated regulation of these interactions is critical both ontogenetically and evolutionarily, and the clinical importance and mechanistic sensitivity to perturbation of this developmental system is reflected by the fact that one-third of all human congenital malformations affect the head and face. Here, we focus on one element of this elaborate process, apoptotic cell death, and its role in normal and abnormal craniofacial development. We highlight four themes in the temporospatial elaboration of craniofacial apoptosis during development, namely its occurrence at (1) positions of epithelial-epithelial apposition, (2) within intra-epithelial morphogenesis, (3) during epithelial compartmentalization, and (4) with CNC metameric organization. Using the genetic perturbation of Satb2, Pbx1/2, Fgf8, and Foxg1 as exemplars, we examine the role of apoptosis in the elaboration of jaw modules, the evolution and elaboration of the lambdoidal junction, the developmental integration at the mandibular arch hinge, and the control of upper jaw identity, patterning and development. Lastly, we posit that apoptosis uniquely acts during craniofacial development to control patterning cues emanating from core organizing centres.
RESUMEN
One of the early, profound insights regarding the biology of the neural crest was the observation of its contribution to the skeletal structures of the cranium and jaws. The critical nature of these structures made the comparative analysis of the cranial neural crest and its derived structures essential investigative aims toward our understanding of the development and evolution of vertebrates and vertebrate-specific structures. Though classically applied to a relatively wide range of taxa in the nineteenth and early twentieth centuries, the application of traditional methodologies for complex comparative developmental and anatomical analyses subsequently become more limited by their time-consuming nature, resource scarcity, and a greater emphasis on the genetic and molecular regulation of patterning and morphogenesis in a select number of tractable model organisms. Recently, however, this trend has been reversed, and the value of genetic and molecular-based questions applied to non-model (unconventional) vertebrate organisms has been re-appreciated. This is particularly true of comparative investigations of cranial neural crest biology. Herein, we present methodologies for the analysis of the cranial neural crest and its structural derivatives employable in modern investigations of both model and unconventional vertebrate organisms.
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Cresta Neural/citología , Animales , Regulación del Desarrollo de la Expresión Génica/fisiología , Microscopía Electrónica de Rastreo , Cresta Neural/ultraestructura , Esqueleto/citología , Esqueleto/ultraestructura , VertebradosRESUMEN
Phylogenetic analyses require evolutionarily independent characters, but there is no consensus, nor has there been a clear methodology presented on how to define character independence in a phylogenetic context, particularly within a complex morphological structure such as the skull. Following from studies of craniofacial development, we hypothesize that the premaxilla is an independent evolutionary module with two integrated characters that have traditionally been treated as independent. We test this hypothesis on a large sample of primate skulls and find evidence supporting the premaxilla as an independent module within the larger module of the palate. Additionally, our data indicate that the convexity of the nasoalveolar clivus and the contour of the alveolus are integrated within the premaxilla. We show that the palate itself is composed of two distinct modules: the FNP-derived premaxillae and the mxBA1-derived maxillae and palatines. Application of our data to early African hominin facial morphology suggests that at least three separate transitions contributed to robust facial morphology: 1) an increase in the size of the post-canine dentition housed within the maxillae and palatines, 2) modification of the premaxilla generating a concave clivus and reduced incisor alveolus, and 3) modification of the zygomatic, shifting the zygomatic root and lateral face anteriorly. These data lend support to the monophyly of Paranthropus boisei and Paranthropus robustus, and provide mounting evidence in favor of a Paranthropus clade. This study also highlights the utility of applying developmental evidence to studies of morphological evolution.
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Evolución Biológica , Cara/anatomía & histología , Maxilar/anatomía & histología , Cráneo/anatomía & histología , Animales , Fósiles , HominidaeRESUMEN
Sorting and degradation of receptors and associated signaling molecules maintain homeostasis of conserved signaling pathways during cell specification and tissue development. Yet, whether machineries that sort signaling proteins act preferentially on different receptors and ligands in different contexts remains mysterious. Here, we show that Vacuolar protein sorting 25, Vps25, a component of ESCRT-II (Endosomal Sorting Complex Required for Transport II), directs preferential endosome-mediated modulation of FGF signaling in limbs. By ENU-induced mutagenesis, we isolated a polydactylous mouse line carrying a hypomorphic mutation of Vps25 (Vps25(ENU)). Unlike Vps25-null embryos we generated, Vps25(ENU/ENU) mutants survive until late gestation. Their limbs display FGF signaling enhancement and consequent hyperactivation of the FGF-SHH feedback loop causing polydactyly, whereas WNT and BMP signaling remain unperturbed. Notably, Vps25(ENU/ENU) Mouse Embryonic Fibroblasts exhibit aberrant FGFR trafficking and degradation; however, SHH signaling is unperturbed. These studies establish that the ESCRT-II machinery selectively limits FGF signaling in vertebrate skeletal patterning.
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Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Endosomas/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Proteínas Hedgehog/metabolismo , Polidactilia/genética , Transducción de Señal , Proteínas de Transporte Vesicular/genética , Animales , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Extremidades/crecimiento & desarrollo , Retroalimentación Fisiológica , Fibroblastos/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutación , Polidactilia/metabolismo , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Much of the gnathostome (jawed vertebrate) evolutionary radiation was dependent on the ability to sense and interpret the environment and subsequently act upon this information through utilization of a specialized mode of feeding involving the jaws. While the gnathostome skull, reflective of the vertebrate baüplan, typically is bilaterally symmetric with right (dextral) and left (sinistral) halves essentially representing mirror images along the midline, both adaptive and abnormal asymmetries have appeared. Herein we provide a basic primer on studies of the asymmetric development of the gnathostome skull, touching briefly on asymmetry as a field of study, then describing the nature of cranial development and finally underscoring evolutionary and functional aspects of left-right asymmetric cephalic development.
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Tipificación del Cuerpo/fisiología , Cráneo/embriología , Vertebrados/embriología , Adaptación Biológica , Animales , Evolución Biológica , Desarrollo Embrionario , Selección GenéticaRESUMEN
BACKGROUND: The Dlx gene family encodes transcription factors involved in the development of a wide variety of morphological innovations that first evolved at the origins of vertebrates or of the jawed vertebrates. This gene family expanded with the two rounds of genome duplications that occurred before jawed vertebrates diversified. It includes at least three bigene pairs sharing conserved regulatory sequences in tetrapods and teleost fish, but has been only partially characterized in chondrichthyans, the third major group of jawed vertebrates. Here we take advantage of developmental and molecular tools applied to the shark Scyliorhinus canicula to fill in the gap and provide an overview of the evolution of the Dlx family in the jawed vertebrates. These results are analyzed in the theoretical framework of the DDC (Duplication-Degeneration-Complementation) model. RESULTS: The genomic organisation of the catshark Dlx genes is similar to that previously described for tetrapods. Conserved non-coding elements identified in bony fish were also identified in catshark Dlx clusters and showed regulatory activity in transgenic zebrafish. Gene expression patterns in the catshark showed that there are some expression sites with high conservation of the expressed paralog(s) and other expression sites with events of paralog sub-functionalization during jawed vertebrate diversification, resulting in a wide variety of evolutionary scenarios within this gene family. CONCLUSION: Dlx gene expression patterns in the catshark show that there has been little neo-functionalization in Dlx genes over gnathostome evolution. In most cases, one tandem duplication and two rounds of vertebrate genome duplication have led to at least six Dlx coding sequences with redundant expression patterns followed by some instances of paralog sub-functionalization. Regulatory constraints such as shared enhancers, and functional constraints including gene pleiotropy, may have contributed to the evolutionary inertia leading to high redundancy between gene expression patterns.
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Secuencia Conservada/genética , Proteínas de Homeodominio/genética , Maxilares/embriología , Factores de Transcripción/genética , Vertebrados/embriología , Vertebrados/genética , Aletas de Animales/embriología , Animales , Encéfalo/embriología , Región Branquial/embriología , Evolución Molecular , Duplicación de Gen/genética , Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/genética , Genoma/genética , Cresta Neural/embriología , Filogenia , ARN no Traducido/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Tiburones/embriología , Tiburones/genética , Pez Cebra/embriología , Pez Cebra/genéticaRESUMEN
The acquisition of jaws constitutes a landmark event in vertebrate evolution, one that in large part potentiated their success and diversification. Jaw development and patterning involves an intricate spatiotemporal series of reciprocal inductive and responsive interactions between the cephalic epithelia and the cranial neural crest (CNC) and cephalic mesodermal mesenchyme. The coordinated regulation of these interactions is critical for both the ontogenetic registration of the jaws and the evolutionary elaboration of variable jaw morphologies and designs. Current models of jaw development and evolution have been built on molecular and cellular evidence gathered mostly in amniotes such as mice, chicks and humans, and augmented by a much smaller body of work on the zebrafish. These have been partnered by essential work attempting to understand the origins of jaws that has focused on the jawless lamprey. Chondrichthyans (cartilaginous fish) are the most distant group to amniotes within extant gnathostomes, and comprise the crucial clade uniting amniotes and agnathans; yet despite their critical phylogenetic position, evidence of the molecular and cellular underpinnings of jaw development in chondrichthyans is still lacking. Recent advances in genome and molecular developmental biology of the lesser spotted dogfish shark, Scyliorhinus canicula, make it ideal for the molecular study of chondrichthyan jaw development. Here, following the 'Hinge and Caps' model of jaw development, we have investigated evidence of heterotopic (relative changes in position) and heterochronic (relative changes in timing) shifts in gene expression, relative to amniotes, in the jaw primordia of S. canicula embryos. We demonstrate the presence of clear proximo-distal polarity in gene expression patterns in the shark embryo, thus establishing a baseline molecular baüplan for branchial arch-derived jaw development and further validating the utility of the 'Hinge and Caps' model in comparative studies of jaw development and evolution. Moreover, we correlate gene expression patterns with the absence of a lambdoidal junction (formed where the maxillary first arch meets the frontonasal processes) in chondrichthyans, further highlighting the importance of this region for the development and evolution of jaw structure in advanced gnathostomes.
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Evolución Biológica , Región Branquial/embriología , Regulación del Desarrollo de la Expresión Génica/fisiología , Maxilares/embriología , Modelos Biológicos , Tiburones/embriología , Factores de Edad , Animales , Cartilla de ADN/genética , Embrión no Mamífero/embriología , Embrión no Mamífero/ultraestructura , Hibridación in Situ , Maxilares/anatomía & histología , Microscopía Electrónica de Rastreo , Filogenia , Tiburones/anatomía & histología , Especificidad de la EspecieRESUMEN
Craniofacial development requires an exquisitely timed and positioned cross-talk between the embryonic cephalic epithelia and mesenchyme. This cross-talk underlies the precise translation of patterning processes and information into distinct, appropriate skeletal morphologies. The molecular and cellular dialogue includes communication via secreted signaling molecules, including Fgf8, and effectors of their interpretation. Herein, we use genetic attenuation of Fgf8 in mice and perform gain-of-function mouse-chick chimeric experiments to demonstrate that significant character states of the frontonasal and optic skeletons are dependent on Fgf8. Notably, we show that the normal orientation and polarity of the nasal capsules and their developing primordia are dependent on Fgf8. We further demonstrate that Fgf8 is required for midfacial integration, and provide evidence for a role for Fgf8 in optic capsular development. Taken together, our data highlight Fgf8 signaling in craniofacial development as a plausible target for evolutionary selective pressures.
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Ojo/embriología , Factor 8 de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Mucosa Nasal/metabolismo , Alelos , Animales , Proliferación Celular , Embrión de Pollo , Ectodermo/metabolismo , Ojo/metabolismo , Genotipo , Etiquetado Corte-Fin in Situ , Ratones , Microscopía Electrónica de Rastreo/métodos , Modelos Biológicos , Transducción de Señal , Factores de TiempoRESUMEN
Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CL/P), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations of WNT, P63, and IRF6 yield CL/P in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CL/P and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CL/P. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair.
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Apoptosis , Células Epiteliales/metabolismo , Cara/embriología , Proteínas de Homeodominio/fisiología , Factores Reguladores del Interferón/metabolismo , Fosfoproteínas/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/fisiología , Proteínas Wnt/metabolismo , Proteína Wnt3/metabolismo , Animales , Secuencia de Bases , Western Blotting , Proliferación Celular , Inmunoprecipitación de Cromatina , Labio Leporino/embriología , Labio Leporino/metabolismo , Fisura del Paladar/embriología , Fisura del Paladar/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Humanos , Técnicas para Inmunoenzimas , Factores Reguladores del Interferón/genética , Luciferasas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Morfogénesis/fisiología , Fenotipo , Fosfoproteínas/genética , Factor de Transcripción 1 de la Leucemia de Células Pre-B , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Ácido Nucleico , Transactivadores/genética , Transfección , Proteínas Wnt/genética , Proteína Wnt3/genéticaRESUMEN
The Alx gene family is implicated in craniofacial development and comprises two to four homeobox genes in each vertebrate genome analyzed. Using phylogenetics and comparative genomics, we show that the common ancestor of jawed vertebrates had three Alx genes descendent from the two-round genome duplications (Alx1, Alx3, Alx4), compared with a single amphioxus gene. Later in evolution one of the paralogues, Alx3, was lost independently from at least three different vertebrate lineages, whereas Alx1 and Alx4 were consistently retained. Comparison of spatial gene expression patterns reveals that the three mouse genes have equivalent craniofacial expression to the two chick and frog genes, suggesting that redundancy compensated for gene loss. We suggest that multiple independent loss of one Alx gene was predisposed by extensive and persistent overlap in gene expression between Alx paralogues. Even so, it is unclear whether it was coincidence or evolutionary bias that resulted in the same Alx gene being lost on each occasion, rather than different members of the gene family.
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Evolución Molecular , Proteínas de Homeodominio/genética , Familia de Multigenes , Filogenia , Vertebrados/genética , Animales , Secuencia Conservada , Embrión de Mamíferos/metabolismo , Embrión no Mamífero/metabolismo , Genómica , Proteínas de Homeodominio/química , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Datos de Secuencia Molecular , Análisis de Secuencia de ADN , Sintenía , Vertebrados/embriologíaRESUMEN
Normal patterning and morphogenesis of the complex skeletal structures of the skull requires an exquisite, reciprocal cross-talk between the embryonic cephalic epithelia and mesenchyme. The mesenchyme associated with the jaws and the optic and olfactory capsules is derived from a Hox-negative cranial neural crest (CNC) population that acts much as an equivalence group in its interactions with specific local cephalic epithelial signals. Craniofacial pattern and morphogenesis is therefore controlled in large part through the regulation of these local cephalic epithelial signals. Here, we demonstrate that Pax6 is essential to the formation and maturation of the complex cephalic ectodermal patterning centers that govern the development and morphogenesis of the upper jaws and associated nasal capsules. Previous examinations of the craniofacial skeletal defects associated with Pax6 mutations have suggested that they arise from an optic-associated blockage in the migration of a specific subpopulation of midbrain CNC to the lateral frontonasal processes. We have addressed an alternative explanation for the craniofacial skeletal defects. We show that in Pax6(SeyN/SeyN) mutants regional CNC is present by E9.25 while there is already specific disruption in the early ontogenetic elaboration of cephalic ectodermal expression, associated with the nascent lambdoidal junction, of secreted signaling factors (including Fgf8 and Bmp4) and transcription factors (including Six1 and Dlx5) essential for upper jaw and/or nasal capsular development. Pax6 therefore regulates craniofacial form, at stages when CNC has just arrived in the frontonasal region, through its control of surface cephalic ectodermal competence to form an essential craniofacial patterning center.
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Anomalías Craneofaciales/genética , Ectodermo/embriología , Proteínas del Ojo/genética , Proteínas de Homeodominio/genética , Desarrollo Maxilofacial/fisiología , Morfogénesis/fisiología , Cresta Neural/fisiología , Factores de Transcripción Paired Box/genética , Proteínas Represoras/genética , Cráneo/embriología , Animales , Anomalías Craneofaciales/patología , Hibridación in Situ , Ratones , Ratones Mutantes , Microscopía Electrónica de Rastreo , Factor de Transcripción PAX6RESUMEN
Modularity is a key mechanism bridging development and evolution and is fundamental to evolvability. Herein, we investigate modularity of the Vertebrate jaw with the aim of understanding mechanisms of its morphological evolution. Conservation of the basic structural bauplan of Vertebrate jaws led to a Hinge and Caps model, in which polarity in the patterning system of developing jaws predicts modularity. We have tested the hypothesis that the Satb2+ cell population delineates a developmental module within the mandibular jaw. Satb2 is expressed in the mesenchyme of the jaw primordia that gives rise to distal elements of both the upper and lower jaws. Loss of Satb2 specifically affects structural elements of the distal (incisor) domain, reflecting the integration of these elements as well as their independence from other mandibular domains. Reducing Satb2 dosage leads to an increase in variation in mandibular length, providing insight into the developmental potential to generate variation. Inter-taxa comparisons reveal that the Satb2 domain is conserved within gnathostomes. We complement previous loss of function studies in mice with gene knock-down experiments in Xenopus, providing evidence for functional conservation of Satb2 in regulating size. Finally, we present evidence that the relative size of the amniote mandibular Satb2+ domain varies in relation to epithelial Fgf8 expression, suggesting a mechanism for evolutionary change in this domain. Taken together, our data support the Hinge and Caps model and provide evidence that Satb2 regulates coordinated distal jaw modules that are subject to evolutionary modification by signals emanating from the Hinge.
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Evolución Biológica , Mandíbula/embriología , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Factores de Transcripción/metabolismo , Animales , Pollos , Factor 8 de Crecimiento de Fibroblastos/genética , Factor 8 de Crecimiento de Fibroblastos/metabolismo , Dosificación de Gen , Regulación del Desarrollo de la Expresión Génica , Variación Genética , Mandíbula/anatomía & histología , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Mesodermo/embriología , Ratones , ARN Mensajero/biosíntesis , Factores de Transcripción/genética , Xenopus , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant or spontaneous disorder characterized by multiple cutaneous basal cell carcinomas, odontogenic keratocysts, skeletal anomalies and facial dysmorphology, including cleft lip and palate. Causative mutations for NBCCS occur in the PTCH1 gene on chromosome 9q22.3-q31, which encodes the principle receptor for the Hedgehog signalling pathway. We have investigated the molecular basis of craniofacial defects seen in NBCCS using a transgenic mouse model expressing Shh in basal epithelium under a Keratin-14 promoter. These mice have an absence of flat bones within the skull vault, hypertelorism, open-bite malocclusion, cleft palate and arrested tooth development. Significantly, increased Hedgehog signal transduction in these mice can influence cell fate within the craniofacial region. In medial edge epithelium of the palate, Shh activity prevents apoptosis and subsequent palatal shelf fusion. In contrast, high levels of Shh in odontogenic epithelium arrests tooth development at the bud stage, secondary to a lack of cell proliferation in this region. These findings illustrate the importance of appropriately regulated Hedgehog signalling during early craniofacial development and demonstrate that oro-facial clefting and hypodontia seen in NBCCS can occur as a direct consequence of increased Shh signal activity within embryonic epithelial tissues.
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Síndrome del Nevo Basocelular/genética , Proteínas Hedgehog/genética , Diente/crecimiento & desarrollo , Anomalías Múltiples/genética , Animales , Síndrome del Nevo Basocelular/patología , Muerte Celular , División Celular , Mapeo Cromosómico , Cromosomas Humanos Par 9 , Fisura del Paladar/genética , Cartilla de ADN , Modelos Animales de Enfermedad , Humanos , Hibridación in Situ , Queratina-14/genética , Meduloblastoma/patología , Ratones , Ratones Transgénicos , Regiones Promotoras Genéticas , Diente/embriología , Diente/patologíaAsunto(s)
Huesos/embriología , Cartílago/embriología , Morfogénesis/fisiología , Coloración y Etiquetado/métodos , Azul Alcián/farmacología , Animales , Antraquinonas/farmacología , Etanol/farmacología , Formaldehído/farmacología , Glicerol/farmacología , Hidróxidos/farmacología , Compuestos de Potasio/farmacología , Fijación del Tejido/métodosRESUMEN
Among the symposia held at the seminal meeting of the European Society for Evolutionary Developmental Biology was one centered on the development and evolution of the vertebrate head, an exquisitely complex anatomical system. The articles presented at this meeting have been gathered in a special issue of the Journal of Experimental Zoology, and are here reviewed by the organizers of the symposia. These articles cover a breadth of subjects, including interactions between cells derived from the different germ layers, such as those underlying neural crest cell migration and fate and cranial muscle specification, as well as placode development and the origin, development, and evolution of important evolutionary innovations such as jaws and the trabecula cranii. In this introduction, we provide a short historical overview of themes of research into the fundamental organization, structure, and development of the vertebrate head, including the search for head segmentation and the relevance of the New Head Hypothesis, and subsequently present the topics discussed in each of the articles. This overview of the past and the present of head evo-devo is then followed by a glimpse at its possible future and a brief examination of the utility of the notions of heterochrony, heterotopy, and heterofacience in describing evolutionarily important changes in developmental events.
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Evolución Biológica , Biología Evolutiva/tendencias , Cabeza/anatomía & histología , Cabeza/embriología , Vertebrados , Animales , Especificidad de la EspecieRESUMEN
Much of what has been written about sutures has either focused on the genetic and biologic etiologies of specific sutural development, maintenance, and pathogenesis or on the utilization of sutures as character states in vertebrate cladistic analyses. There is a much more modest literature explicitly concerned with the evolution of sutures. We provide a small bridge of these literatures by presenting a discussion of the evolutionary biologic bases for the patterns of where, when, and how sutural boundaries between skeletal and dental elements have been established and have evolved. As sutural boundaries do not exist in the absence of the nucleation events that initiate the generation of skeletal elements, we explore historic models seeking to identify the inductive events dictating the specific times and places where a cranial skeletal element forms, the elaboration of its sutural boundaries, and the mechanisms whereby subsequent phyletic changes may be manifested and recognized.
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Suturas Craneales/anatomía & histología , Animales , Evolución Biológica , Suturas Craneales/fisiología , Humanos , Paleontología , Fenotipo , Filogenia , Cráneo/anatomía & histología , Cráneo/fisiologíaRESUMEN
Tooth development is a complex process including successive stages of initiation, morphogenesis, and histogenesis. The role of the Dlx family of homeobox genes during the early stages of tooth development has been widely analyzed, while little data has been reported on their role in dental histogenesis. The expression pattern of Dlx2 has been described in the mouse incisor; an inverse linear relationship exists between the level of Dlx2 expression and enamel thickness, suggesting a role for Dlx2 in regulation of ameloblast differentiation and activity. In vitro data have revealed that DLX homeoproteins are able to regulate the expression of matrix proteins such as osteocalcin. The aim of the present study was to analyze the expression and function of Dlx genes during amelogenesis. Analysis of Dlx2/LacZ transgenic reporter mice, Dlx2 and Dlx1/Dlx2 null mutant mice, identified spatial variations in Dlx2 expression within molar tooth germs and suggests a role for Dlx2 in the organization of preameloblastic cells as a palisade in the labial region of molars. Later, during the secretory and maturation stages of amelogenesis, the expression pattern in molars was found to be similar to that described in incisors. The expression patterns of the other Dlx genes were examined in incisors and compared to Dlx2. Within the ameloblasts Dlx3 and Dlx6 are expressed constantly throughout presecretory, secretory, and maturation stages; during the secretory phase when Dlx2 is transitorily switched off, Dlx1 expression is upregulated. These data suggest a role for DLX homeoproteins in the morphological control of enamel. Sequence analysis of the amelogenin gene promoter revealed five potential responsive elements for DLX proteins that are shown to be functional for DLX2. Regulation of amelogenin in ameloblasts may be one method by which DLX homeoproteins may control enamel formation. To conclude, this study establishes supplementary functions of Dlx family members during tooth development: the participation in establishment of dental epithelial functional organization and the control of enamel morphogenesis via regulation of amelogenin expression.
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Amelogenina/metabolismo , Esmalte Dental/fisiología , Proteínas de Homeodominio/metabolismo , Diente , Factores de Transcripción/metabolismo , Amelogénesis/fisiología , Amelogenina/genética , Animales , Secuencia de Bases , Esmalte Dental/citología , Regulación del Desarrollo de la Expresión Génica , Genes Reporteros , Proteínas de Homeodominio/genética , Hibridación in Situ , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Regiones Promotoras Genéticas , Diente/anatomía & histología , Diente/crecimiento & desarrollo , Factores de Transcripción/genéticaRESUMEN
Historically, examinations of gnathostome skulls have indicated that for essentially the entirety of their existence, jaws have been characterized by a high degree of fidelity to an initial basic structural design that will then go on to manifest an amazing array of end-point phenotypes. These two traits-bauplan fidelity and elaboration of design-are inter-connected and striking, and beg a number of questions, including: Are all jaws made in the same manner and if not how not? To begin to tackle such questions, we herein operationally define jaws as two appositional, hinged cranial units for which polarity and potential modularity are characteristics, and then address what is necessary for them to form, including delineating both the sources of cells and tissues that will formally yield the jaws as well as what informs their ontogeny (e.g., sources of positional information and factors directing the interpretation of developmental cues). Following on this, we briefly describe a predictive, testable model of jaw development (the "Hinge and Caps" model) and present evidence that the Satb2+cell population in the developing jaw primordia of mice defines a developmentally and evolutionarily significant jaw module such as would be predicted by the model.
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Evolución Biológica , Maxilares/anatomía & histología , Maxilares/embriología , Modelos Biológicos , Morfogénesis/fisiología , Vertebrados/embriología , Animales , Especificidad de la EspecieRESUMEN
INTRODUCTIONDue to their large size and long generation times, chondrichthyans have been largely ignored by geneticists. However, their key phylogenetic position makes them ideal subjects to study the molecular bases of the important morphological and physiological innovations that characterize jawed vertebrates. Such analyses are crucial to understanding the origin of the complex genetic mechanisms unraveled in osteichthyans. The small spotted dogfish Scyliorhinus canicula, a representative of the largest order of extant sharks, presents a number of advantages in this context. Due to its relatively small size among sharks, its abundance, and easy maintenance, the dogfish has been an important model in comparative anatomy and physiology for more than a century. Recently, revived interest has occurred with the development of large-scale transcriptomic and genomic resources, together with the establishment of facilities allowing massive egg and embryo production. These new tools open the way to molecular analyses of the elaborate physiological and sensory systems used by sharks. They also make it possible to take advantage of unique characteristics of these species, such as organ zonation, in analyses of cell proliferation and differentiation. Finally, they offer important perspectives to evolutionary developmental biology that will provide a better understanding of the origin and diversifications of jawed vertebrates. The dogfish whole-genome sequence, which may shortly become accessible, should establish this species as an essential shark reference, complementary to other chondrichthyan models. These analyses are likely to reveal an organism of an underestimated complexity, far from the primitive prototypical gnathostome anticipated in gradistic views.
RESUMEN
Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves. Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice. As growth arrest-specific 1 (Gas1) encodes a membrane glycoprotein previously identified as a Shh antagonist in the somite, we analyzed the craniofacial phenotype of mice harboring a targeted Gas1 deletion. Gas1(-/-) mice exhibited microform HPE, including midfacial hypoplasia, premaxillary incisor fusion, and cleft palate, in addition to severe ear defects; however, gross integrity of the forebrain remained intact. These defects were associated with partial loss of Shh signaling in cells at a distance from the source of transcription, suggesting that Gas1 can potentiate hedgehog signaling in the early face. Loss of a single Shh allele in a Gas1(-/-) background significantly exacerbated the midline craniofacial phenotype, providing genetic evidence that Shh and Gas1 interact. As human GAS1 maps to chromosome 9q21.3-q22, a region previously associated with nonsyndromic cleft palate and congenital deafness, our results establish GAS1 as a potential locus for several human craniofacial malformations.