Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 30
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Clin Genet ; 106(2): 209-213, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38693682

RESUMEN

SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that Satb2 is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. Satb2-/- mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.


Asunto(s)
Región Branquial , Proteínas de Unión a la Región de Fijación a la Matriz , Fenotipo , Factores de Transcripción , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Animales , Humanos , Ratones , Factores de Transcripción/genética , Región Branquial/anomalías , Región Branquial/patología , Anomalías Craneofaciales/genética , Anomalías Craneofaciales/patología , Femenino , Masculino , Ratones Noqueados , Síndrome , Mandíbula/anomalías , Mandíbula/patología
2.
Am J Med Genet A ; 194(2): 203-210, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37786328

RESUMEN

Alterations in SATB2 result in SATB2-associated syndrome (SAS; Glass syndrome, OMIM 612313), an autosomal dominant multisystemic disorder predominantly characterized by developmental delay, craniofacial anomalies, and growth retardation. The bone phenotype of SAS has been less explored until recently and includes a variety of skeletal deformities, increased risk of low bone mineral density (BMD) with a propensity to fractures, and other biochemical abnormalities that suggest elevated bone turnover. We present the results of ongoing surveillance of bone health from 32 individuals (47% females, 3-18 years) with molecularly-confirmed SAS evaluated at a multidisciplinary clinic. Five individuals (5/32, 16%) were documented to have BMD Z-scores by DXA scans of -2.0 SD or lower and 7 more (7/32, 22%) had Z-scores between -1 and - 2 SD at the lumbar spine or the total hip. Alkaline phosphatase levels were found to be elevated in 19 individuals (19/30, 63%) and determined to correspond to bone-specific alkaline phosphatase elevations when measured (11/11, 100%). C-telopeptide levels were found to be elevated when adjusted by age and gender in 6 individuals (6/14, 43%). Additionally, the two individuals who underwent bone cross-sectional geometry evaluation by peripheral quantitative computed tomography were documented to have low cortical bone density for age and sex despite concurrent DXA scans that did not have this level of decreased density. While we could not identify particular biochemical abnormalities that predicted low BMD, the frequent elevations in markers of bone formation and resorption further confirmed the increased bone turnover in SAS. Based on our results and other recently published studies, we propose surveillance guidelines for the skeletal phenotype of SAS.


Asunto(s)
Enfermedades Óseas Metabólicas , Proteínas de Unión a la Región de Fijación a la Matriz , Femenino , Humanos , Masculino , Densidad Ósea/genética , Fosfatasa Alcalina , Estudios Prospectivos , Huesos/diagnóstico por imagen , Absorciometría de Fotón/métodos , Síndrome , Factores de Transcripción/genética , Proteínas de Unión a la Región de Fijación a la Matriz/genética
3.
Hum Mol Genet ; 30(9): 739-757, 2021 05 28.
Artículo en Inglés | MEDLINE | ID: mdl-33601405

RESUMEN

EFTUD2 is mutated in patients with mandibulofacial dysostosis with microcephaly (MFDM). We generated a mutant mouse line with conditional mutation in Eftud2 and used Wnt1-Cre2 to delete it in neural crest cells. Homozygous deletion of Eftud2 causes brain and craniofacial malformations, affecting the same precursors as in MFDM patients. RNAseq analysis of embryonic heads revealed a significant increase in exon skipping and increased levels of an alternatively spliced Mdm2 transcript lacking exon 3. Exon skipping in Mdm2 was also increased in O9-1 mouse neural crest cells after siRNA knock-down of Eftud2 and in MFDM patient cells. Moreover, we found increased nuclear P53, higher expression of P53-target genes and increased cell death. Finally, overactivation of the P53 pathway in Eftud2 knockdown cells was attenuated by overexpression of non-spliced Mdm2, and craniofacial development was improved when Eftud2-mutant embryos were treated with Pifithrin-α, an inhibitor of P53. Thus, our work indicates that the P53-pathway can be targeted to prevent craniofacial abnormalities and shows a previously unknown role for alternative splicing of Mdm2 in the etiology of MFDM.


Asunto(s)
Ribonucleoproteína Nuclear Pequeña U5 , Proteína p53 Supresora de Tumor , Animales , Homocigoto , Humanos , Ratones , Mutación , Factores de Elongación de Péptidos/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Ribonucleoproteína Nuclear Pequeña U5/genética , Eliminación de Secuencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
4.
Dev Dyn ; 251(10): 1711-1727, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35618654

RESUMEN

BACKGROUND: Asymmetries in craniofacial anomalies are commonly observed. In the facial skeleton, the left side is more commonly and/or severely affected than the right. Such asymmetries complicate treatment options. Mechanisms underlying variation in disease severity between individuals as well as within individuals (asymmetries) are still relatively unknown. RESULTS: Developmental reductions in fibroblast growth factor 8 (Fgf8) have a dosage dependent effect on jaw size, shape, and symmetry. Further, Fgf8 mutants have directionally asymmetric jaws with the left side being more affected than the right. Defects in lower jaw development begin with disruption to Meckel's cartilage, which is discontinuous. All skeletal elements associated with the proximal condensation are dysmorphic, exemplified by a malformed and misoriented malleus. At later stages, Fgf8 mutants exhibit syngnathia, which falls into two broad categories: bony fusion of the maxillary and mandibular alveolar ridges and zygomatico-mandibular fusion. All of these morphological defects exhibit both inter- and intra-specimen variation. CONCLUSIONS: We hypothesize that these asymmetries are linked to heart development resulting in higher levels of Fgf8 on the right side of the face, which may buffer the right side to developmental perturbations. This mouse model may facilitate future investigations of mechanisms underlying human syngnathia and facial asymmetry.


Asunto(s)
Región Branquial , Corazón , Animales , Factor 8 de Crecimiento de Fibroblastos/genética , Humanos , Anomalías Maxilomandibulares , Maxilar , Ratones , Anomalías de la Boca
5.
Semin Cell Dev Biol ; 91: 13-22, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-29248471

RESUMEN

The skull is a vertebrate novelty. Morphological adaptations of the skull are associated with major evolutionary transitions, including the shift to a predatory lifestyle and the ability to masticate while breathing. These adaptations include the chondrocranium, dermatocranium, articulated jaws, primary and secondary palates, internal choanae, the middle ear, and temporomandibular joint. The incredible adaptive diversity of the vertebrate skull indicates an underlying bauplan that promotes evolvability. Comparative studies in craniofacial development suggest that the craniofacial bauplan includes three secondary organizers, two that are bilaterally placed at the Hinge of the developing jaw, and one situated in the midline of the developing face (the FEZ). These organizers regulate tissue interactions between the cranial neural crest, the neuroepithelium, and facial and pharyngeal epithelia that regulate the development and evolvability of the craniofacial skeleton.


Asunto(s)
Evolución Biológica , Huesos Faciales/embriología , Cresta Neural/embriología , Cráneo/embriología , Animales , Tipificación del Cuerpo/genética , Huesos Faciales/anatomía & histología , Huesos Faciales/metabolismo , Peces/anatomía & histología , Peces/embriología , Peces/genética , Regulación del Desarrollo de la Expresión Génica , Cresta Neural/anatomía & histología , Cresta Neural/metabolismo , Cráneo/anatomía & histología , Cráneo/metabolismo
6.
Semin Cell Dev Biol ; 88: 67-79, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-29782925

RESUMEN

Canalization, or robustness to genetic or environmental perturbations, is fundamental to complex organisms. While there is strong evidence for canalization as an evolved property that varies among genotypes, the developmental and genetic mechanisms that produce this phenomenon are very poorly understood. For evolutionary biology, understanding how canalization arises is important because, by modulating the phenotypic variation that arises in response to genetic differences, canalization is a determinant of evolvability. For genetics of disease in humans and for economically important traits in agriculture, this subject is important because canalization is a potentially significant cause of missing heritability that confounds genomic prediction of phenotypes. We review the major lines of thought on the developmental-genetic basis for canalization. These fall into two groups. One proposes specific evolved molecular mechanisms while the other deals with robustness or canalization as a more general feature of development. These explanations for canalization are not mutually exclusive and they overlap in several ways. General explanations for canalization are more likely to involve emergent features of development than specific molecular mechanisms. Disentangling these explanations is also complicated by differences in perspectives between genetics and developmental biology. Understanding canalization at a mechanistic level will require conceptual and methodological approaches that integrate quantitative genetics and developmental biology.


Asunto(s)
Evolución Biológica , Epigénesis Genética , Epistasis Genética , Estudios de Asociación Genética , Genotipo , Fenotipo , Adaptación Fisiológica/genética , Animales , Biología Evolutiva/métodos , Redes Reguladoras de Genes , Interacción Gen-Ambiente , Técnicas Genéticas , Variación Genética , Genética , Humanos , Plantas/genética , Carácter Cuantitativo Heredable , Selección Genética
7.
Clin Genet ; 99(4): 547-557, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33381861

RESUMEN

SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Proteínas de Unión a la Región de Fijación a la Matriz/deficiencia , Factores de Transcripción/deficiencia , Adulto , Niño , Preescolar , Cromosomas Humanos Par 2/ultraestructura , Colágeno Tipo III/deficiencia , Colágeno Tipo III/genética , Colágeno Tipo V/deficiencia , Colágeno Tipo V/genética , Enanismo/genética , Cara/anomalías , Femenino , Estudios de Asociación Genética , Edad Gestacional , Humanos , Hipertensión Pulmonar/genética , Lactante , Masculino , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Microcefalia/genética , Fenotipo , Delgadez/genética , Factores de Transcripción/genética
8.
Genesis ; 57(1): e23249, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30207415

RESUMEN

Variation in development mediates phenotypic differences observed in evolution and disease. Although the mechanisms underlying phenotypic variation are still largely unknown, recent research suggests that variation in developmental processes may play a key role. Developmental processes mediate genotype-phenotype relationships and consequently play an important role regulating phenotypes. In this review, we provide an example of how shared and interacting developmental processes may explain convergence of phenotypes in spliceosomopathies and ribosomopathies. These data also suggest a shared pathway to disease treatment. We then discuss three major mechanisms that contribute to variation in developmental processes: genetic background (gene-gene interactions), gene-environment interactions, and developmental stochasticity. Finally, we comment on evolutionary alterations to developmental processes, and the evolution of disease buffering mechanisms.


Asunto(s)
Desarrollo Óseo/genética , Disostosis Craneofacial/genética , Evolución Molecular , Regulación del Desarrollo de la Expresión Génica , Animales , Disostosis Craneofacial/metabolismo , Humanos , Empalme del ARN , Ribosomas/genética , Cráneo/embriología , Cráneo/metabolismo
9.
Hum Mutat ; 40(8): 1013-1029, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31021519

RESUMEN

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.


Asunto(s)
Proteínas de Unión a la Región de Fijación a la Matriz/genética , Mutación , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Adolescente , Animales , Niño , Preescolar , Codón de Terminación , Modelos Animales de Enfermedad , Femenino , Reordenamiento Génico , Estudios de Asociación Genética , Humanos , Masculino , Mutación Missense , Polimorfismo de Nucleótido Simple
10.
Dev Biol ; 415(2): 188-197, 2016 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-26724698

RESUMEN

Craniofacial disease phenotypes exhibit significant variation in penetrance and severity. Although many genetic contributions to phenotypic variation have been identified, genotype-phenotype correlations remain imprecise. Recent work in evolutionary developmental biology has exposed intriguing developmental mechanisms that potentially explain incongruities in genotype-phenotype relationships. This review focuses on two observations from work in comparative and experimental animal model systems that highlight how development structures variation. First, multiple genetic inputs converge on relatively few developmental processes. Investigation of when and how variation in developmental processes occurs may therefore help predict potential genetic interactions and phenotypic outcomes. Second, genetic mutation is typically associated with an increase in phenotypic variance. Several models outlining developmental mechanisms underlying mutational increases in phenotypic variance are discussed using Satb2-mediated variation in jaw size as an example. These data highlight development as a critical mediator of genotype-phenotype correlations. Future research in evolutionary developmental biology focusing on tissue-level processes may help elucidate the "black box" between genotype and phenotype, potentially leading to novel treatment, earlier diagnoses, and better clinical consultations for individuals affected by craniofacial anomalies.


Asunto(s)
Anomalías Craneofaciales/genética , Estudios de Asociación Genética , Desarrollo Maxilofacial/fisiología , Animales , Evolución Biológica , Evolución Molecular , Cara/embriología , Regulación del Desarrollo de la Expresión Génica , Técnicas de Silenciamiento del Gen , Variación Genética , Cabeza/embriología , Humanos , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/fisiología , Desarrollo Maxilofacial/genética , Mesodermo/citología , Mesodermo/embriología , Morfogénesis , Mutación , Cresta Neural/citología , Cresta Neural/embriología , Cráneo/embriología , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Vertebrados/embriología , Vertebrados/genética
11.
Development ; 141(3): 674-84, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24449843

RESUMEN

Variation in jaw size during evolution has been crucial for the adaptive radiation of vertebrates, yet variation in jaw size during development is often associated with disease. To test the hypothesis that early developmental events regulating neural crest (NC) progenitors contribute to species-specific differences in size, we investigated mechanisms through which two avian species, duck and quail, achieve their remarkably different jaw size. At early stages, duck exhibit an anterior shift in brain regionalization yielding a shorter, broader, midbrain. We find no significant difference in the total number of pre-migratory NC; however, duck concentrate their pre-migratory NC in the midbrain, which contributes to an increase in size of the post-migratory NC population allocated to the mandibular arch. Subsequent differences in proliferation lead to a progressive increase in size of the duck mandibular arch relative to that of quail. To test the role of pre-migratory NC progenitor number in regulating jaw size, we reduced and augmented NC progenitors. In contrast to previous reports of regeneration by NC precursors, we find that neural fold extirpation results in a loss of NC precursors. Despite this reduction in their numbers, post-migratory NC progenitors compensate, producing a symmetric and normal-sized jaw. Our results suggest that evolutionary modification of multiple aspects of NC cell biology, including NC allocation within the jaw primordia and NC-mediated proliferation, have been important to the evolution of jaw size. Furthermore, our finding of NC post-migratory compensatory mechanisms potentially extends the developmental time frame for treatments of disease or injury associated with NC progenitor loss.


Asunto(s)
Patos/anatomía & histología , Maxilares/anatomía & histología , Desarrollo Maxilofacial , Codorniz/anatomía & histología , Animales , Encéfalo/anatomía & histología , Movimiento Celular , Proliferación Celular , Regulación del Desarrollo de la Expresión Génica , Mandíbula/anatomía & histología , Mandíbula/citología , Mandíbula/crecimiento & desarrollo , Cresta Neural/citología , Tamaño de los Órganos , Especificidad de la Especie
12.
Am J Med Genet A ; 173(2): 327-337, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27774744

RESUMEN

The SATB2-associated syndrome is a recently described syndrome characterized by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities. Alterations of the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point mutations. The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines. The SATB2-associated syndrome registry has now been started and that will allow gathering further clinical information and refining the provided surveillance recommendations. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.


Asunto(s)
Estudios de Asociación Genética , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Fenotipo , Factores de Transcripción/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Animales , Deleción Cromosómica , Cromosomas Humanos Par 2 , Discapacidades del Desarrollo/diagnóstico , Discapacidades del Desarrollo/genética , Estudios de Asociación Genética/métodos , Pruebas Genéticas , Genómica/métodos , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Proteínas de Unión a la Región de Fijación a la Matriz/química , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Mutación , Vigilancia de la Población , Síndrome , Factores de Transcripción/química , Factores de Transcripción/metabolismo
13.
Am J Med Genet A ; 173(4): 985-1006, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28168819

RESUMEN

The Society for Craniofacial Genetics and Developmental Biology (SCGDB) aims to promote education, research, and communication, about normal and abnormal development of the tissues and organs of the head. Membership of the SCGDB is broad and diverse-including clinicians, orthodontists, scientists, and academics-but with all members sharing an interest in craniofacial biology. Each year, the SCGDB hosts a meeting where members can share their latest research, exchange ideas and resources, and build on or establish new collaborations. © 2017 Wiley Periodicals, Inc.


Asunto(s)
Anomalías Craneofaciales/genética , Biología Evolutiva/educación , Regulación del Desarrollo de la Expresión Génica , Evolución Biológica , Boston , Anomalías Craneofaciales/patología , Anomalías Craneofaciales/terapia , Biología Evolutiva/historia , Biología Evolutiva/tendencias , Historia del Siglo XXI , Humanos , Defensa del Paciente/educación
14.
J Hum Evol ; 77: 143-54, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25449953

RESUMEN

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 , Hominidae
15.
Proc Natl Acad Sci U S A ; 107(38): 16595-600, 2010 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-20823249

RESUMEN

Mutations in ASPM (abnormal spindle-like microcephaly associated) cause primary microcephaly in humans, a disorder characterized by a major reduction in brain size in the apparent absence of nonneurological anomalies. The function of the Aspm protein in neural progenitor cell expansion, as well as its localization to the mitotic spindle and midbody, suggest that it regulates brain development by a cell division-related mechanism. Furthermore, evidence that positive selection affected ASPM during primate evolution has led to suggestions that such a function changed during primate evolution. Here, we report that in Aspm mutant mice, truncated Aspm proteins similar to those causing microcephaly in humans fail to localize to the midbody during M-phase and cause mild microcephaly. A human ASPM transgene rescues this phenotype but, interestingly, does not cause a gain of function. Strikingly, truncated Aspm proteins also cause a massive loss of germ cells, resulting in a severe reduction in testis and ovary size accompanied by reduced fertility. These germline effects, too, are fully rescued by the human ASPM transgene, indicating that ASPM is functionally similar in mice and humans. Our findings broaden the spectrum of phenotypic effects of ASPM mutations and raise the possibility that positive selection of ASPM during primate evolution reflects its function in the germline.


Asunto(s)
Microcefalia/genética , Mutación , Proteínas del Tejido Nervioso/genética , Animales , Animales Recién Nacidos , Secuencia de Bases , Encéfalo/anomalías , Proteínas de Unión a Calmodulina , Cartilla de ADN/genética , Modelos Animales de Enfermedad , Células Madre Embrionarias/patología , Femenino , Mutación de Línea Germinal , Humanos , Infertilidad/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Ratones Transgénicos , Microcefalia/patología , Proteínas del Tejido Nervioso/fisiología , Neuronas/patología , Oligospermia/genética , Ovario/anomalías , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/fisiología , Fenotipo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Eliminación de Secuencia , Motilidad Espermática/genética , Testículo/anomalías
16.
Front Cell Dev Biol ; 11: 1186526, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37287454

RESUMEN

Introduction: The pharyngeal arches are transient developmental structures that, in vertebrates, give rise to tissues of the head and neck. A critical process underlying the specification of distinct arch derivatives is segmentation of the arches along the anterior-posterior axis. Formation of ectodermal-endodermal interfaces is a key mediator of this process, and although it is essential, mechanisms regulating the establishment of these interfaces vary between pouches and between taxa. Methods: Here, we focus on the patterning and morphogenesis of epithelia associated with the first pharyngeal arch, the first pharyngeal pouch (pp1) and the first pharyngeal cleft (pc1), and the role of Fgf8 dosage in these processes in the mouse model system. Results: We find that severe reductions of Fgf8 levels disrupt both pp1 and pc1 development. Notably, out-pocketing of pp1 is largely robust to Fgf8 reductions, however, pp1 extension along the proximal-distal axis fails when Fgf8 is low. Our data indicate that Fgf8 is required for specification of regional identity in both pp1 and pc1, for localized changes in cell polarity, and for elongation and extension of both pp1 and pc1. Discussion: Based on Fgf8-mediated changes in tissue relationships between pp1 and pc1, we hypothesize that extension of pp1 requires physical interaction with pc1. Overall, our data indicate a critical role for the lateral surface ectoderm in segmentation of the first pharyngeal arch that has previously been under-appreciated.

17.
bioRxiv ; 2023 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-36993764

RESUMEN

The pharyngeal arches are transient developmental structures that, in vertebrates, give rise to tissues of the head and neck. A critical process underlying the specification of distinct arch derivatives is segmentation of the arches along the anterior-posterior axis. Out-pocketing of the pharyngeal endoderm between the arches is a key mediator of this process, and although it is essential, mechanisms regulating out-pocketing vary between pouches and between taxa. Here, we focus on the patterning and morphogenesis of epithelia associated with the first pharyngeal arch, the first pharyngeal pouch (pp1) and the first pharyngeal cleft (pc1), and the role of Fgf8 dosage in these processes. We find that severe reductions of Fgf8 levels disrupt both pp1 and pc1 development. Notably, out-pocketing of pp1 is largely robust to Fgf8 reductions, however, pp1 extension along the proximal-distal axis fails when Fgf8 is low. Our data indicate that extension of pp1 requires physical interaction with pc1, and that multiple aspects of pc1 morphogenesis require Fgf8 . In particular, Fgf8 is required for specification of regional identity in both pp1 and pc1, for localized changes in cell polarity, and for elongation and extension of both pp1 and pc1. Overall, our data indicate a critical role for the lateral surface ectoderm in segmentation of the first pharyngeal arch that has previously been under-appreciated.

18.
Genesis ; 49(4): 307-25, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21309073

RESUMEN

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 PAX6
19.
Evol Dev ; 13(4): 343-51, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21740507

RESUMEN

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/embriología
20.
Evol Dev ; 13(6): 549-64, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-23016939

RESUMEN

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/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA