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1.
Am J Hum Genet ; 101(6): 985-994, 2017 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-29198724

RESUMEN

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.


Asunto(s)
Proteína Morfogenética Ósea 2/genética , Anomalías Craneofaciales/genética , Discapacidades del Desarrollo/genética , Enanismo/genética , Haploinsuficiencia/genética , Cardiopatías Congénitas/genética , Animales , Huesos/embriología , Niño , Preescolar , Cromosomas Humanos Par 20/genética , Fisura del Paladar/genética , Modelos Animales de Enfermedad , Femenino , Corazón/embriología , Humanos , Lactante , Masculino , Ratones , Ratones Noqueados , Factor de Crecimiento Transformador beta/genética
2.
Growth Factors ; 36(1-2): 58-68, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-30035654

RESUMEN

Ryk is a member of the receptor tyrosine kinase (RTK) family of proteins that control and regulate cellular processes. It is distinguished by binding Wnt ligands and having no detectable intrinsic protein tyrosine kinase activity suggesting Ryk is a pseudokinase. Here, we show an essential role for Ryk in directing morphogenetic events required for normal cardiac development through the examination of Ryk-deficient mice. We employed vascular corrosion casting, vascular perfusion with contrast dye, and immunohistochemistry to characterize cardiovascular and pharyngeal defects in Ryk-/- embryos. Ryk-/- mice exhibit a variety of malformations of the heart and outflow tract that resemble human congenital heart defects. This included stenosis and interruption of the aortic arch, ventriculoarterial malalignment, ventricular septal defects and abnormal pharyngeal arch artery remodelling. This study therefore defines a key intersection between a subset of growth factor receptors involved in planar cell polarity signalling, the Wnt family and mammalian cardiovascular development.


Asunto(s)
Cardiopatías Congénitas/etiología , Faringe/anomalías , Proteínas Tirosina Quinasas Receptoras/fisiología , Proteínas Wnt/metabolismo , Animales , Aorta Torácica/anomalías , Femenino , Ratones , Morfogénesis , Embarazo
3.
Am J Med Genet A ; 176(6): 1349-1368, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29696787

RESUMEN

The triad of micrognathia, glossoptosis, and concomitant airway obstruction defined as "Robin sequence" (RS) is caused by oropharyngeal developmental events constrained by a reduced stomadeal space. This sequence of abnormal embryonic development also results in an anatomical configuration that might predispose the fetus to a cleft palate. RS is heterogeneous and many different etiologies have been described including syndromic, RS-plus, and isolated forms. For an optimal diagnosis, subsequent treatment and prognosis, a thorough understanding of the embryology and pathogenesis is necessary. This manuscript provides an update about our current understanding of the development of the mandible, tongue, and palate and possible mechanisms involved in the development of RS. Additionally, we provide the reader with an up-to-date summary of the different etiologies of this phenotype and link this to the embryologic, developmental, and genetic mechanisms.


Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Mandíbula/embriología , Hueso Paladar/embriología , Síndrome de Pierre Robin/etiología , Lengua/embriología , Femenino , Humanos , Síndrome de Pierre Robin/fisiopatología , Embarazo
4.
PLoS Genet ; 9(8): e1003746, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-24009529

RESUMEN

Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies.


Asunto(s)
Proteínas Portadoras/genética , Comunicación Celular/genética , Cilios/patología , Síndrome de Ellis-Van Creveld/genética , Desarrollo Embrionario/genética , Animales , Polaridad Celular , Cilios/genética , Modelos Animales de Enfermedad , Síndrome de Ellis-Van Creveld/patología , Proteínas Hedgehog/genética , Humanos , Ratones , Mutación , Transducción de Señal
5.
Dev Dyn ; 244(8): 1022-30, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-26061551

RESUMEN

BACKGROUND: The YPEL (Yippee-like) gene family comprises five highly conserved members (YPEL1-5), but their biological function remains largely unknown. Early studies of YPEL1 function suggested that it plays a role in the development of structures derived from the pharyngeal arches. Human YPEL1 localises to distal chromosome 22q11.2 and copy number changes at this locus lead to diverse phenotypes that include facial dysmorphism, facial asymmetry, and palatal anomalies comprising the distal 22q11.2 deletion/duplication syndromes (OMIM 611867). We therefore investigated the role of chick YPEL1 in craniofacial development using ex vivo and in vivo approaches in the avian model. RESULTS: We found that retroviral-mediated in vivo overexpression of YPEL1 causes abnormal mandibular morphogenesis associated with increased apoptosis and involvement of the BMP/MSX pathway. CONCLUSIONS: Our results suggest that YPEL1 expression is regulated by bone morphogenetic protein signaling and suggest a role for YPEL1 in the pathogenesis of the craniofacial abnormalities observed in humans with distal chromosome 22q11.2 deletions or duplications.


Asunto(s)
Proteínas Aviares/metabolismo , Huesos Faciales/embriología , Huesos Faciales/metabolismo , Animales , Proteínas Aviares/genética , Pollos , Morfogénesis/genética , Morfogénesis/fisiología , Activación Transcripcional
6.
Nature ; 461(7261): 267-71, 2009 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-19710650

RESUMEN

Sex in birds is chromosomally based, as in mammals, but the sex chromosomes are different and the mechanism of avian sex determination has been a long-standing mystery. In the chicken and all other birds, the homogametic sex is male (ZZ) and the heterogametic sex is female (ZW). Two hypotheses have been proposed for the mechanism of avian sex determination. The W (female) chromosome may carry a dominant-acting ovary determinant. Alternatively, the dosage of a Z-linked gene may mediate sex determination, two doses being required for male development (ZZ). A strong candidate avian sex-determinant under the dosage hypothesis is the conserved Z-linked gene, DMRT1 (doublesex and mab-3-related transcription factor 1). Here we used RNA interference (RNAi) to knock down DMRT1 in early chicken embryos. Reduction of DMRT1 protein expression in ovo leads to feminization of the embryonic gonads in genetically male (ZZ) embryos. Affected males show partial sex reversal, characterized by feminization of the gonads. The feminized left gonad shows female-like histology, disorganized testis cords and a decline in the testicular marker, SOX9. The ovarian marker, aromatase, is ectopically activated. The feminized right gonad shows a more variable loss of DMRT1 and ectopic aromatase activation, suggesting differential sensitivity to DMRT1 between left and right gonads. Germ cells also show a female pattern of distribution in the feminized male gonads. These results indicate that DMRT1 is required for testis determination in the chicken. Our data support the Z dosage hypothesis for avian sex determination.


Asunto(s)
Pollos/genética , Pollos/fisiología , Caracteres Sexuales , Cromosomas Sexuales/genética , Procesos de Determinación del Sexo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Animales , Biomarcadores/análisis , Línea Celular , Embrión de Pollo , Trastornos del Desarrollo Sexual , Regulación hacia Abajo , Femenino , Dosificación de Gen/genética , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Modelos Genéticos , Ovario/embriología , Ovario/metabolismo , Interferencia de ARN , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Testículo/embriología , Testículo/metabolismo , Factores de Transcripción/deficiencia
7.
Dev Biol ; 370(1): 145-53, 2012 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-22884497

RESUMEN

Twist1 has been demonstrated to play critical roles in the early development of neural crest and mesodermally derived tissues including the limb. Twist2 has been less well characterised but its relatively late onset of expression suggests specific roles in the development of a number of organs. Expression of Twist2 within the developing limbs begins after formation of the limb bud and persists within the peripheral mesenchyme until digital rays condense. We have used RCAS-mediated overexpression in chick to investigate the function of Twist2 in limb development. Viral misexpression following injection into the lateral plate mesoderm results in a spectrum of hypoplastic limb phenotypes. These include generalized shortening of the entire limb, fusion of the autopod skeletal elements, loss of individual digits or distal truncation resulting in complete loss of the autopod. These phenotypes appear to result from a premature termination of limb outgrowth and manifest as defective growth in both the proximal-distal and anterior-posterior axes. In situ hybridisation analysis demonstrates that many components of the Shh/Grem1/Fgf regulatory loop that controls early limb growth and patterning are downregulated by Twist2 overexpression. Grem1 has a complementary expression pattern to Twist2 within the limb primordia and co-expression of both Grem1 and Twist2 results in a rescue of the Twist2 overexpression phenotype. We demonstrate that Twist proteins directly repress Grem1 expression via a regulatory element downstream of the open reading frame. These data indicate that Twist2 regulates early limb morphogenesis through a role in terminating the Shh/Grem1/Fgf autoregulatory loop.


Asunto(s)
Tipificación del Cuerpo/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Esbozos de los Miembros/embriología , Fenotipo , Proteína 1 Relacionada con Twist/metabolismo , Animales , Secuencia de Bases , Embrión de Pollo , Inmunoprecipitación de Cromatina , Clonación Molecular , Cartilla de ADN/genética , Ensayo de Cambio de Movilidad Electroforética , Regulación del Desarrollo de la Expresión Génica/genética , Hibridación in Situ , Etiquetado Corte-Fin in Situ , Datos de Secuencia Molecular , Sistemas de Lectura Abierta/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Proteína 1 Relacionada con Twist/genética
8.
Am J Med Genet C Semin Med Genet ; 163C(4): 295-305, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-24127256

RESUMEN

Pierre Robin sequence (PRS) is a craniofacial anomaly comprising mandibular hypoplasia, cleft secondary palate and glossoptosis leading to life-threatening obstructive apnea and feeding difficulties during the neonatal period. The respiratory issues require careful management and in severe cases may require extended stays in neonatal intensive care units and surgical intervention such as lengthening the lower jaw or tracheotomy to relieve airway obstruction. These feeding and respiratory complications frequently continue well into childhood, affecting not only growth and development but also impacting on long term educational attainment. The diagnosis of PRS depends on readily recognizable clinical features but the phenotypic similarity of many PRS individuals conceals considerable etiological heterogeneity. Defects in the growth of the mandible sit at the core of PRS and the natural history of PRS can be classified into two major streams: primary defects of mandibular outgrowth and elongation and issues that are external to the mandibular skeleton but that secondarily impact on its growth. These altered developmental trajectories appear to be driven by a range of influences including defects in cartilage growth, neuromuscular function and fetal constraint. Various genetic and cytogenetic associations have been made with PRS and the diversity of these associations highlights the fact that there are numerous ways to arrive at this common phenotypic endpoint.


Asunto(s)
Obstrucción de las Vías Aéreas/fisiopatología , Apnea/fisiopatología , Fisura del Paladar/fisiopatología , Síndrome de Pierre Robin/fisiopatología , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/cirugía , Apnea/etiología , Apnea/cirugía , Fisura del Paladar/cirugía , Humanos , Cuidado Intensivo Neonatal , Mandíbula/patología , Fenotipo , Síndrome de Pierre Robin/genética , Síndrome de Pierre Robin/cirugía
9.
Am J Med Genet A ; 155A(7): 1623-33, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21671380

RESUMEN

The availability of microarray technology has led to the recent recognition of copy number abnormalities of distal chromosome 22q11.2 that are distinct from the better-characterized deletions and duplications of the proximal region. This report describes five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2. We report on novel phenotypic features including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome; and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. We describe the third distal chromosome 22q11.2 microdeletion patient with Goldenhar syndrome. Patients with distal chromosome 22q11.2 copy number abnormalities exhibit inter- and intra-familial phenotypic variability, and challenge our ability to draw meaningful genotype-phenotype correlations.


Asunto(s)
Cromosomas Humanos Par 22/genética , Variaciones en el Número de Copia de ADN/genética , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Síndrome de Goldenhar/genética , Humanos , Lactante , Recién Nacido , Masculino , Secuencias Repetitivas de Ácidos Nucleicos/genética , Adulto Joven
10.
Evol Dev ; 12(5): 459-73, 2010.
Artículo en Inglés | MEDLINE | ID: mdl-20883215

RESUMEN

Dlx homeodomain transcription factors are expressed in neural crest-derived mesenchyme of the pharyngeal arches and are required for patterning of the craniofacial skeleton. However, the cellular and molecular mechanisms by which Dlx factors control skeletogenesis in the facial primordia are unclear. We have investigated the function of Dlx2 and Dlx5 by sustained misexpression in ovo. We find that RCAS-Dlx2- and RCAS-Dlx5-infected avian embryos exhibit very similar patterns of local, stereotypical changes in skeletal development in the upper jaw. The changes include ectopic dermal bone along the jugal arch, and ectopic cartilages that develop between the quadrate and the trabecula. The ectopic cartilage associated with the trabecula is reminiscent of a normally occurring element in this region in some bird taxa. Analysis of the distribution of RCAS-Dlx2-infected cells suggests that Dlx2 induces aggregation of undifferentiated mesenchyme, which subsequently develops into the ectopic skeletal elements. Comparison of infected embryos with restricted or widespread misexpression, and of embryos in which Dlx genes were delivered to migratory or postmigratory neural crest, indicate that there are limited regions of competence in which the ectopic elements can arise. The site-specific differentiation program that the aggregates undergo may be dependent on local environmental signals. Our results suggest that Dlx factors mediate localization of ectomesenchymal subpopulations within the pharyngeal arches and in doing so define where skeletogenic condensations will arise. Consequently, variation in Dlx expression or activity may have influenced the morphology of jaw elements during vertebrate evolution.


Asunto(s)
Proteínas Aviares/fisiología , Tipificación del Cuerpo/genética , Desarrollo Embrionario/genética , Proteínas de Homeodominio/fisiología , Maxilares/embriología , Factores de Transcripción/fisiología , Animales , Proteínas Aviares/genética , Proteínas Aviares/metabolismo , Región Branquial/crecimiento & desarrollo , Región Branquial/metabolismo , Región Branquial/patología , Cartílago/embriología , Cartílago/crecimiento & desarrollo , Cartílago/patología , Diferenciación Celular/genética , Embrión de Pollo , Pollos/genética , Pollos/crecimiento & desarrollo , Pollos/metabolismo , Ectodermo/crecimiento & desarrollo , Ectodermo/metabolismo , Ectodermo/patología , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Maxilares/patología , Mesodermo/crecimiento & desarrollo , Mesodermo/metabolismo , Mesodermo/patología , Codorniz/embriología , Codorniz/genética , Codorniz/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
11.
BMC Dev Biol ; 9: 20, 2009 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-19272164

RESUMEN

BACKGROUND: During vertebrate embryogenesis the initial stages of bone formation by endochondral ossification involve the aggregation and proliferation of mesenchymal cells into condensations. Continued growth of the condensations and differentiation of the mesenchymal cells into chondrocytes results in the formation of cartilage templates, or anlagen, which prefigure the shape of the future bones. The chondrocytes in the anlagen further differentiate by undergoing a complex sequence of maturation and hypertrophy, and are eventually replaced by mineralized bone. Regulation of the onset of chondrogenesis is incompletely understood, and would be informed by comprehensive analyses of in vivo gene expression. RESULTS: Tibial and fibular pre-condensed mesenchyme was microdissected from mouse hind limbs at 11.5 dpc, and the corresponding condensations at 12.5 dpc and cartilage anlagen at 13.5 dpc. Total RNA was isolated, and cRNA generated by linear amplification was interrogated using mouse whole genome microarrays. Differential expression was validated by quantitative PCR for Agc1, Bmp8a, Col2a1, Fgfr4, Foxa3, Gdf5, Klf2, Klf4, Lepre1, Ncad, Sox11, and Trpv4. Further, independent validation of the microarray data was achieved by in situ hybridization to analyse the expression of Lepre1, Pcdh8, Sox11, and Trpv4 from 11.5 dpc to 13.5 dpc during mouse hind limb development. We found significant differential expression of 931 genes during these early stages of chondrogenesis. Of these, 380 genes were down-regulated and 551 up-regulated. Our studies characterized the expression pattern of gene families previously associated with chondrogenesis, such as adhesion molecules, secreted signalling molecules, transcription factors, and extracellular matrix components. Gene ontology approaches identified 892 differentially expressed genes not previously identified during the initiation of chondrogenesis. These included several Bmp, Gdf, Wnt, Sox and Fox family members. CONCLUSION: These data represent the first global gene expression profiling analysis of chondrogenic tissues during in vivo development. They identify genes for further study on their functional roles in chondrogenesis, and provide a comprehensive and important resource for future studies on cartilage development and disease.


Asunto(s)
Condrogénesis , Desarrollo Embrionario , Regulación del Desarrollo de la Expresión Génica , Esbozos de los Miembros/embriología , Animales , Perfilación de la Expresión Génica , Factor 4 Similar a Kruppel , Organogénesis
12.
Matrix Biol ; 27(4): 295-305, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18314316

RESUMEN

WARP is a recently described member of the von Willebrand factor A domain superfamily of extracellular matrix proteins, and is encoded by the Vwa1 gene. We have previously shown that WARP is a multimeric component of the chondrocyte pericellular matrix in articular cartilage and intervertebral disc, where it interacts with the basement membrane heparan sulfate proteoglycan perlecan. However, the tissue-specific expression of WARP in non-cartilaginous tissues and its localization in the extracellular matrix of other perlecan-containing tissues have not been analyzed in detail. To visualize WARP-expressing cells, we generated a reporter gene knock-in mouse by targeted replacement of the Vwa1 gene with beta-galactosidase. Analysis of reporter gene expression and WARP protein localization by immunostaining demonstrates that WARP is a component of a limited number of distinct basement membranes. WARP is expressed in the vasculature of neural tissues and in basement membrane structures of the peripheral nervous system. Furthermore, WARP is also expressed in the apical ectodermal ridge of developing limb buds, and in skeletal and cardiac muscle. These findings are the first evidence for WARP expression in non-cartilaginous tissues, and the identification of WARP as a component of a limited range of specialized basement membranes provides further evidence for the heterogeneous composition of basement membranes between different tissues.


Asunto(s)
Membrana Basal/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Embrión de Mamíferos/embriología , Embrión de Mamíferos/metabolismo , Proteínas de la Matriz Extracelular/genética , Femenino , Regulación del Desarrollo de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Especificidad de Órganos
13.
Nat Commun ; 8(1): 132, 2017 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-28743862

RESUMEN

The ratites are a distinctive clade of flightless birds, typified by the emu and ostrich that have acquired a range of unique anatomical characteristics since diverging from basal Aves at least 100 million years ago. The emu possesses a vestigial wing with a single digit and greatly reduced forelimb musculature. However, the embryological basis of wing reduction and other anatomical changes associated with loss of flight are unclear. Here we report a previously unknown co-option of the cardiac transcription factor Nkx2.5 to the forelimb in the emu embryo, but not in ostrich, or chicken and zebra finch, which have fully developed wings. Nkx2.5 is expressed in emu limb bud mesenchyme and maturing wing muscle, and mis-expression of Nkx2.5 throughout the limb bud in chick results in wing reductions. We propose that Nkx2.5 functions to inhibit early limb bud expansion and later muscle growth during development of the vestigial emu wing.The transcription factor Nkx2.5 is essential for heart development. Here, the authors identify a previously unknown expression domain for Nkx2.5 in the emu wing and explore its role in diminished wing bud development in the flightless emu, compared with three other birds that have functional wings.


Asunto(s)
Proteínas Aviares/genética , Proteína Homeótica Nkx-2.5/genética , Factores de Transcripción/genética , Alas de Animales/metabolismo , Animales , Proteínas Aviares/metabolismo , Dromaiidae , Miembro Anterior/embriología , Miembro Anterior/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica , Hibridación in Situ , Esbozos de los Miembros/embriología , Esbozos de los Miembros/metabolismo , Mesodermo/embriología , Mesodermo/metabolismo , Músculo Esquelético/embriología , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Alas de Animales/embriología
14.
Mol Syndromol ; 7(6): 312-321, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27920634

RESUMEN

The complex anatomy of the skull and face arises from the requirement to support multiple sensory and structural functions. During embryonic development, the diverse component elements of the neuro- and viscerocranium must be generated independently and subsequently united in a manner that sustains and promotes the growth of the brain and sensory organs, while achieving a level of structural integrity necessary for the individual to become a free-living organism. While each of these individual craniofacial components is essential, the cranial and facial midline lies at a structural nexus that unites these disparately derived elements, fusing them into a whole. Defects of the craniofacial midline can have a profound impact on both form and function, manifesting in a diverse array of phenotypes and clinical entities that can be broadly defined as frontonasal dysplasias (FNDs). Recent advances in the identification of the genetic basis of FNDs along with the analysis of developmental mechanisms impacted by these mutations have dramatically altered our understanding of this complex group of conditions.

15.
Mol Syndromol ; 7(6): 322-328, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27920635

RESUMEN

Pierre Robin Sequence (PRS) is usually classified into syndromic and nonsyndromic groups, with a further subclassification of the nonsyndromic group into isolated PRS and PRS with additional anomalies (PRS-Plus). The aim of this research is to provide an accurate phenotypic characterisation of nonsyndromic PRS, specifically the PRS-Plus subgroup. We sought to examine the frequency of sequence variants in previously defined conserved noncoding elements (CNEs) in the putative enhancer region upstream of SOX9, the regulation of which has been associated with PRS phenotypes. We identified 141 children with nonsyndromic PRS at the Royal Children's Hospital, Melbourne from 1985 to 2012 using 2 databases. Clinical and demographic data were extracted by file review and children categorized as 'isolated PRS' or 'PRS-Plus'. A subset of children with PRS-Plus was selected for detailed phenotyping and DNA sequencing of the upstream SOX9 CNEs. We found 83 children with isolated PRS and 58 with PRS-Plus. The most common PRS-Plus malformations involved the musculoskeletal and ocular systems. The most common coexisting craniofacial malformation was choanal stenosis/atresia. We identified 10 children with a family history of PRS or cleft palate. We found a single nucleotide substitution in a putative GATA1-binding site in one patient, but it was inherited from his phenotypically unaffected mother. PRS-Plus represents a broad phenotypic spectrum with uncertain pathogenesis. Dysmorphology assessment by a clinical geneticist is recommended. SOX9 CNE sequence variants are rare in our cohort and are unlikely to play a significant role in the pathogenesis of PRS-Plus.

16.
Evodevo ; 7: 26, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-28031782

RESUMEN

BACKGROUND: The forelimb of the flightless emu is a vestigial structure, with greatly reduced wing elements and digit loss. To explore the molecular and cellular mechanisms associated with the evolution of vestigial wings and loss of flight in the emu, key limb patterning genes were examined in developing embryos. METHODS: Limb development was compared in emu versus chicken embryos. Immunostaining for cell proliferation markers was used to analyze growth of the emu forelimb and hindlimb buds. Expression patterns of limb patterning genes were studied, using whole-mount in situ hybridization (for mRNA localization) and RNA-seq (for mRNA expression levels). RESULTS: The forelimb of the emu embryo showed heterochronic development compared to that in the chicken, with the forelimb bud being retarded in its development. Early outgrowth of the emu forelimb bud is characterized by a lower level of cell proliferation compared the hindlimb bud, as assessed by PH3 immunostaining. In contrast, there were no obvious differences in apoptosis in forelimb versus hindlimb buds (cleaved caspase 3 staining). Most key patterning genes were expressed in emu forelimb buds similarly to that observed in the chicken, but with smaller expression domains. However, expression of Sonic Hedgehog (Shh) mRNA, which is central to anterior-posterior axis development, was delayed in the emu forelimb bud relative to other patterning genes. Regulators of Shh expression, Gli3 and HoxD13, also showed altered expression levels in the emu forelimb bud. CONCLUSIONS: These data reveal heterochronic but otherwise normal expression of most patterning genes in the emu vestigial forelimb. Delayed Shh expression may be related to the small and vestigial structure of the emu forelimb bud. However, the genetic mechanism driving retarded emu wing development is likely to rest within the forelimb field of the lateral plate mesoderm, predating the expression of patterning genes.

17.
JAMA Pediatr ; 170(9): 894-902, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27429161

RESUMEN

IMPORTANCE: Robin sequence (RS) is a congenital condition characterized by micrognathia, glossoptosis, and upper airway obstruction. Currently, no consensus exists regarding the diagnosis and evaluation of children with RS. An international, multidisciplinary consensus group was formed to begin to overcome this limitation. OBJECTIVE: To report a consensus-derived set of best practices for the diagnosis and evaluation of infants with RS as a starting point for defining standards and management. EVIDENCE REVIEW: Based on a literature review and expert opinion, a clinical consensus report was generated. FINDINGS: Because RS can occur as an isolated condition or as part of a syndrome or multiple-anomaly disorder, the diagnostic process for each newborn may differ. Micrognathia is hypothesized as the initiating event, but the diagnosis of micrognathia is subjective. Glossoptosis and upper airway compromise complete the primary characteristics of RS. It can be difficult to judge the severity of tongue base airway obstruction, and the possibility of multilevel obstruction exists. The initial assessment of the clinical features and severity of respiratory distress is important and has practical implications. Signs of upper airway obstruction can be intermittent and are more likely to be present when the infant is asleep. Therefore, sleep studies are recommended. Feeding problems are common and may be exacerbated by the presence of a cleft palate. The clinical features and their severity can vary widely and ultimately dictate the required investigations and treatments. CONCLUSIONS AND RELEVANCE: Agreed-on recommendations for the initial evaluation of RS and clinical descriptors are provided in this consensus report. Researchers and clinicians will ideally use uniform definitions and comparable assessments. Prospective studies and the standard application of validated assessments are needed to build an evidence base guiding standards of care for infants and children with RS.


Asunto(s)
Consenso , Síndrome de Pierre Robin/diagnóstico , Guías de Práctica Clínica como Asunto , Diagnóstico Diferencial , Humanos , Lactante , Recién Nacido
18.
Gene Expr Patterns ; 19(1-2): 30-5, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26116001

RESUMEN

BACKGROUND: Olfactory receptors were initially believed to be expressed specifically within the olfactory neurons. However, accumulating genome-scale data has recently demonstrated more extensive expression. There are hundreds of olfactory receptor family members and the realisation of their widespread expression provides an opportunity to reveal new biology. However, existing data is predominantly based on RT-PCR, microarray and RNA-seq approaches and the details of tissue and cell-type specific expression are lacking. RESULTS: As a proof of principle, we selected Olfr603 for expression analysis. We generated an antibody against a non-conserved epitope of Olfr603 and characterised its expression in E8.5-E12.5 mouse embryos using immunohistochemistry. This analysis demonstrated a dynamic pattern of expression in diverse cell types within the developing embryo unrelated to the olfactory system. Expression was detected in migrating neural crest, endothelial precursors and vascular endothelium, endocardial cells, smooth muscle, neuroepithelium and within the ocular tissues. This complex distribution does not conform to any apparent germ layer or tissue origin. CONCLUSIONS: This initial characterisation of Olfr603 expression highlights the potential for a broad role for this receptor in the development of many tissues.


Asunto(s)
Neuronas Receptoras Olfatorias/metabolismo , Receptores Nucleares Huérfanos/biosíntesis , Receptores Odorantes/biosíntesis , Secuencia de Aminoácidos , Animales , Embrión de Mamíferos , Expresión Génica , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Proteínas del Tejido Nervioso/biosíntesis , Sistema Nervioso/metabolismo , Cresta Neural/metabolismo , Tubo Neural/metabolismo , Vías Olfatorias/metabolismo
19.
Gene Expr Patterns ; 5(1): 75-9, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15533821

RESUMEN

Members of the ADAM gene family encode large multi-domain proteins containing A Disintegrin And Metalloprotease domain. We have cloned quail orthologs of ADAM 12 and 19 using PCR-based screening and describe their expression patterns over the period E2.5 (Hamilton and Hamburger stage 14) to E5.0 (HH 25) using in situ hybridisation. Quail ADAM 12 is expressed in mesenchyme, cranially, in the tail and in the limb buds, and also in visceral mesenchyme. In the nervous system it is expressed in dorsal root ganglia and ventral roots. Quail ADAM 19 is expressed in cranial and dorsal root ganglia, sympathetic ganglia, ventral mixed nerves and in the allantois. Avian ADAM 12 and 19 genes exhibit similarities and differences in expression pattern compared to their murine orthologs, for example, expression of ADAM 12 in the nervous system, limb and tail bud in quail but not mouse. Interestingly, in mouse ADAM 19 is expressed in these locations. We have generated a sheep antibody to quail ADAM 19 and, in embryonic cells in vitro, found the protein at cell-cell junctions in many cell types. Some of these did have detectable ADAM 19 by in situ hybridisation but RT-PCR analysis confirmed the presence of low level ADAM 19 transcripts not detectable by in situ hybridisation.


Asunto(s)
Coturnix/genética , Desintegrinas/genética , Proteínas de la Membrana/genética , Metaloendopeptidasas/genética , Proteínas ADAM , Proteína ADAM12 , Animales , Northern Blotting , Coturnix/embriología , Coturnix/metabolismo , ADN Complementario , Desintegrinas/biosíntesis , Desintegrinas/aislamiento & purificación , Ganglios Sensoriales/embriología , Ganglios Sensoriales/enzimología , Corazón/embriología , Inmunohistoquímica , Hibridación in Situ , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/aislamiento & purificación , Metaloendopeptidasas/biosíntesis , Metaloendopeptidasas/aislamiento & purificación , Miocardio/enzimología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
20.
Mol Syndromol ; 5(6): 276-86, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25565927

RESUMEN

The 22q11.2 deletion syndrome (22q11DS) is thought to be a contiguous gene syndrome caused by haploinsufficiency for a variable number of genes with overlapping function during the development of the craniofacial, pharyngeal and cardiac structures. The complexity of genetic and developmental anomalies resulting in 22q11DS has made attributing causation to specific genes difficult. The CRKL gene resides within the common 3-Mb region, most frequently affected in 22q11DS, and has been shown to play an essential role in the development of tissues affected in 22q11DS. Here, we report the characterisation of a mouse strain we named 'snoopy', harbouring a novel Crkl splice-site mutation that results in a loss of Crkl expression. The snoopy strain exhibits a variable phenotype that includes micrognathia, pharyngeal occlusion, aglossia and holoprosencephaly, and altered retinoic acid and endothelin signalling. Together, these features are reminiscent of malformations occurring in auriculocondylar syndrome and agnathia-otocephaly complex, 2 conditions not previously associated with the CRKL function. Comparison of the features of a cohort of patients harbouring small 22q11.2 deletions centred over the CRKL gene, but sparing TBX1, highlights the role of CRKL in contributing to the craniofacial features of 22q11DS. These analyses demonstrate the central role of Crkl in regulating signalling events in the developing oropharyngeal complex and its potential to contribute to dysmorphology.

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