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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
Tipificación del Cuerpo/fisiología , Cráneo/embriología , Vertebrados/embriología , Adaptación Biológica , Animales , Evolución Biológica , Desarrollo Embrionario , Selección 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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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.
Asunto(s)
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/metabolismoAsunto(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.
Asunto(s)
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.
Asunto(s)
Suturas Craneales/anatomía & histología , Animales , Evolución Biológica , Suturas Craneales/fisiología , Humanos , Paleontología , Fenotipo , Filogenia , Cráneo/anatomía & histología , Cráneo/fisiologíaRESUMEN
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
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.
Asunto(s)
Proteínas de Ciclo Celular/genética , Proteínas Hedgehog/genética , Holoprosencefalia/genética , Proteínas de la Membrana/genética , Animales , Anomalías Craneofaciales/embriología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Femenino , Proteínas Ligadas a GPI , Proteínas Hedgehog/deficiencia , Holoprosencefalia/embriología , Holoprosencefalia/patología , Humanos , Masculino , Proteínas de la Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Embarazo , Transducción de SeñalRESUMEN
The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous--along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.
Asunto(s)
Dosificación de Gen , Maxilares/embriología , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Hueso Paladar/embriología , Factores de Transcripción/genética , Animales , Apoptosis , Southern Blotting , Fisura del Paladar/genética , Anomalías Craneofaciales/genética , Exones , Femenino , Eliminación de Gen , Regulación del Desarrollo de la Expresión Génica , Marcación de Gen , Hibridación in Situ , Maxilares/fisiología , Proteínas de Unión a la Región de Fijación a la Matriz/fisiología , Ratones , Ratones Endogámicos C57BL , Modelos Anatómicos , Hueso Paladar/fisiología , Embarazo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/fisiologíaRESUMEN
Classic neontology (comparative embryology and anatomy), through the application of the concept of homology, has demonstrated that the development of the gnathostome (jawed vertebrate) skull is characterized both by a fidelity to the gnathostome bauplan and the exquisite elaboration of final structural design. Just as homology is an old concept amended for modern purposes, so are many of the questions regarding the development of the skull. With due deference to Geoffroy-St. Hilaire, Cuvier, Owen, Lankester et al., we are still asking: How are bauplan fidelity and elaboration of design maintained, coordinated, and modified to generate the amazing diversity seen in cranial morphologies? What establishes and maintains pattern in the skull? Are there universal developmental mechanisms underlying gnathostome autapomorphic structural traits? Can we detect and identify the etiologies of heterotopic (change in the topology of a developmental event), heterochronic (change in the timing of a developmental event), and heterofacient (change in the active capacetence, or the elaboration of capacity, of a developmental event) changes in craniofacial development within and between taxa? To address whether jaws are all made in a like manner (and if not, then how not), one needs a starting point for the sake of comparison. To this end, we present here a "hinge and caps" model that places the articulation, and subsequently the polarity and modularity, of the upper and lower jaws in the context of cranial neural crest competence to respond to positionally located epithelial signals. This model expands on an evolving model of polarity within the mandibular arch and seeks to explain a developmental patterning system that apparently keeps gnathostome jaws in functional registration yet tractable to potential changes in functional demands over time. It relies upon a system for the establishment of positional information where pattern and placement of the "hinge" is driven by factors common to the junction of the maxillary and mandibular branches of the first arch and of the "caps" by the signals emanating from the distal-most first arch midline and the lamboidal junction (where the maxillary branch meets the frontonasal processes). In this particular model, the functional registration of jaws is achieved by the integration of "hinge" and "caps" signaling, with the "caps" sharing at some critical level a developmental history that potentiates their own coordination. We examine the evidential foundation for this model in mice, examine the robustness with which it can be applied to other taxa, and examine potential proximate sources of the signaling centers. Lastly, as developmental biologists have long held that the anterior-most mesendoderm (anterior archenteron roof or prechordal plate) is in some way integral to the normal formation of the head, including the cranial skeletal midlines, we review evidence that the seminal patterning influences on the early anterior ectoderm extend well beyond the neural plate and are just as important to establishing pattern within the cephalic ectoderm, in particular for the "caps" that will yield medial signaling centers known to coordinate jaw development.
Asunto(s)
Cráneo/anatomía & histología , Cráneo/embriología , Animales , Animales Recién Nacidos , Humanos , Recién Nacido , Mandíbula/anatomía & histología , Mandíbula/embriología , Maxilar/anatomía & histología , Maxilar/embriologíaRESUMEN
The branchial arches are meristic vertebrate structures, being metameric both between each other within the rostrocaudal series along the ventrocephalic surface of the embryonic head and within each individual arch: thus, just as each branchial arch must acquire a unique identity along the rostrocaudal axis, each structure within the proximodistal axis of an arch must also acquire a unique identity. It is believed that regional specification of metameric structures is controlled by the nested expression of related genes resulting in a regional code, a principal that is though to be demonstrated by the regulation of rostrocaudal axis development in animals exerted by the nested HOM-C/Hox homeobox genes. The nested expression pattern of the Dlx genes within the murine branchial arch ectomesenchyme has more recently led to the proposal of a Dlx code for the regional specification along the proximodistal axis of the branchial arches (i.e. it establishes intra-arch identity). This review re-examines this hypothesis, and presents new work on an allelic series of Dlx loss-of-function mouse mutants that includes various combinations of Dlx1, Dlx2, Dlx3, Dlx5 and Dlx6. Although we confirm fundamental aspects of the hypothesis, we further report a number of novel findings. First, contrary to initial reports, Dlx1, Dlx2 and Dlx1/2 heterozygotes exhibit alterations of branchial arch structures and Dlx2-/- and Dlx1/2-/- mutants have slight alterations of structures derived from the distal portions of their branchial arches. Second, we present evidence for a role for murine Dlx3 in the development of the branchial arches. Third, analysis of compound Dlx mutants reveals four grades of mandibular arch transformations and that the genetic interactions of cis first-order (e.g. Dlx5 and Dlx6), trans second-order (e.g. Dlx5 and Dlx2) and trans third-order paralogues (e.g. Dlx5 and Dlx1) result in significant and distinct morphological differences in mandibular arch development. We conclude by integrating functions of the Dlx genes within the context of a hypothesized general mechanism for the establishment of pattern and polarity in the first branchial arch of gnathostomes that includes regionally secreted growth factors such as Fgf8 and Bmp and other transcription factors such as Msx1, and is consistent both with the structure of the conserved gnathostome jaw bauplan and the elaboration of this bauplan to meet organismal end-point designs.
Asunto(s)
Huesos/embriología , Región Branquial/fisiología , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Factores de Transcripción/genética , Animales , Anomalías Craneofaciales/genética , Genotipo , Humanos , Maxilares/embriología , Ratones , Ratones Mutantes , Modelos Animales , Morfogénesis/genética , FenotipoRESUMEN
Monosomy of the human chromosome 6p terminal region results in a variety of congenital malformations that include brain, craniofacial, and organogenesis abnormalities. To examine the genetic basis of these phenotypes, we have carried out an unbiased functional analysis of the syntenic region of the mouse genome (proximal Mmu13). A genetic screen for recessive mutations in this region recovered thirteen lines with phenotypes relevant to a variety of clinical conditions. These include two loci that cause holoprosencephaly, two that underlie anophthalmia, one of which also contributes to other craniofacial abnormalities such as microcephaly, agnathia, and palatogenesis defects, and one locus responsible for developmental heart and kidney defects. Analysis of heterozygous carriers of these mutations shows that a high proportion of these loci manifest with behavioral activity and sensorimotor deficits in the heterozygous state. This finding argues for the systematic, reciprocal phenotypic assessment of dominant and recessive mouse mutants. In addition to providing a resource of single gene mutants that model 6p-associated disorders, the work reveals unsuspected genetic complexity at this region. In particular, many of the phenotypes associated with 6p deletions can be elicited by mutation in one of a number of genes. This finding implies that phenotypes associated with contiguous gene deletion syndromes can result not only from dosage sensitivity of one gene in the region but also from the combined effect of monosomy for multiple genes that function within the same biological process.