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1.
Cell ; 185(1): 95-112.e18, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34995520

RESUMO

Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.


Assuntos
Dermatoglifia , Dedos/crescimento & desenvolvimento , Organogênese/genética , Polimorfismo de Nucleotídeo Único , Dedos do Pé/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Povo Asiático/genética , Padronização Corporal/genética , Criança , Estudos de Coortes , Feminino , Membro Anterior/crescimento & desenvolvimento , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Proteína do Locus do Complexo MDS1 e EVI1/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Adulto Jovem
2.
Cell ; 180(6): 1262-1271.e15, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32169219

RESUMO

Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants.


Assuntos
Elementos Facilitadores Genéticos/genética , Ensaios de Triagem em Larga Escala/métodos , Polidactilia/genética , Animais , Elementos Facilitadores Genéticos/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas de Introdução de Genes/métodos , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Camundongos , Mutação , Fenótipo , Polidactilia/metabolismo , RNA não Traduzido/genética
3.
Cell ; 167(3): 633-642.e11, 2016 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-27768887

RESUMO

The evolution of body shape is thought to be tightly coupled to changes in regulatory sequences, but specific molecular events associated with major morphological transitions in vertebrates have remained elusive. We identified snake-specific sequence changes within an otherwise highly conserved long-range limb enhancer of Sonic hedgehog (Shh). Transgenic mouse reporter assays revealed that the in vivo activity pattern of the enhancer is conserved across a wide range of vertebrates, including fish, but not in snakes. Genomic substitution of the mouse enhancer with its human or fish ortholog results in normal limb development. In contrast, replacement with snake orthologs caused severe limb reduction. Synthetic restoration of a single transcription factor binding site lost in the snake lineage reinstated full in vivo function to the snake enhancer. Our results demonstrate changes in a regulatory sequence associated with a major body plan transition and highlight the role of enhancers in morphological evolution. PAPERCLIP.


Assuntos
Evolução Biológica , Elementos Facilitadores Genéticos , Extremidades/crescimento & desenvolvimento , Proteínas Hedgehog/genética , Serpentes/genética , Animais , Sequência de Bases , Evolução Molecular , Técnicas de Introdução de Genes , Camundongos , Camundongos Transgênicos , Mutação , Filogenia , Serpentes/classificação
4.
Genes Dev ; 37(7-8): 261-276, 2023 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-36990510

RESUMO

Congenital genetic disorders affecting limb morphology in humans and other mammals are particularly well described, due to both their rather high frequencies of occurrence and the ease of their detection when expressed as severe forms. In most cases, their molecular and cellular etiology remained unknown long after their initial description, often for several decades, and sometimes close to a century. Over the past 20 yr, however, experimental and conceptual advances in our understanding of gene regulation, in particular over large genomic distances, have allowed these cold cases to be reopened and, eventually, for some of them to be solved. These investigations led not only to the isolation of the culprit genes and mechanisms, but also to the understanding of the often complex regulatory processes that are disturbed in such mutant genetic configurations. Here, we present several cases in which dormant regulatory mutations have been retrieved from the archives, starting from a historical perspective up to their molecular explanations. While some cases remain open, waiting for new tools and/or concepts to bring their investigations to an end, the solutions to others have contributed to our understanding of particular features often found in the regulation of developmental genes and hence can be used as benchmarks to address the impact of noncoding variants in the future.


Assuntos
Genoma , Mamíferos , Animais , Humanos , Mutação
5.
Genes Dev ; 35(21-22): 1490-1509, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34711654

RESUMO

Mammalian Hox gene clusters contain a range of CTCF binding sites. In addition to their importance in organizing a TAD border, which isolates the most posterior genes from the rest of the cluster, the positions and orientations of these sites suggest that CTCF may be instrumental in the selection of various subsets of contiguous genes, which are targets of distinct remote enhancers located in the flanking regulatory landscapes. We examined this possibility by producing an allelic series of cumulative in cis mutations in these sites, up to the abrogation of CTCF binding in the five sites located on one side of the TAD border. In the most impactful alleles, the global chromatin architecture of the locus was modified, yet not drastically, illustrating that CTCF sites located on one side of a strong TAD border are sufficient to organize at least part of this insulation. Spatial colinearity in the expression of these genes along the major body axis was nevertheless maintained, despite abnormal expression boundaries. In contrast, strong effects were scored in the selection of target genes responding to particular enhancers, leading to the misregulation of Hoxd genes in specific structures. Altogether, while most enhancer-promoter interactions can occur in the absence of this series of CTCF sites, the binding of CTCF in the Hox cluster is required to properly transform a rather unprecise process into a highly discriminative mechanism of interactions, which is translated into various patterns of transcription accompanied by the distinctive chromatin topology found at this locus. Our allelic series also allowed us to reveal the distinct functional contributions for CTCF sites within this Hox cluster, some acting as insulator elements, others being necessary to anchor or stabilize enhancer-promoter interactions, and some doing both, whereas they all together contribute to the formation of a TAD border. This variety of tasks may explain the amazing evolutionary conservation in the distribution of these sites among paralogous Hox clusters or between various vertebrates.


Assuntos
Cromatina , Elementos Facilitadores Genéticos , Animais , Sítios de Ligação , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Cromatina/genética , Elementos Facilitadores Genéticos/genética , Genes Homeobox/genética , Mamíferos/genética , Camundongos , Mutagênese
6.
Genes Dev ; 35(21-22): 1401-1402, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34725128

RESUMO

In this issue of Genes & Development, Amândio and colleagues (pp. 1490-1509) dissect the function of a cluster of several CTCF binding sites in the HoxD cluster by iterative deletions in mice. They found additive functions for some, and intriguingly found that some sites function as insulators, while others function as anchors for enhancer-promoter interactions. These functions vary depending on developmental context. The work provides new insights into the roles played by CTCF in regulating developmental patterns and 3D chromatin organization.


Assuntos
Cromatina , Elementos Facilitadores Genéticos , Animais , Sítios de Ligação/genética , Fator de Ligação a CCCTC/genética , Fator de Ligação a CCCTC/metabolismo , Cromatina/genética , Elementos Facilitadores Genéticos/genética , Proteínas de Homeodomínio , Camundongos , Regiões Promotoras Genéticas/genética
7.
Dev Biol ; 512: 1-10, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38657748

RESUMO

Precise regulation of gene expression is of utmost importance during cell fate specification. DNA methylation is a key epigenetic mechanism that plays a significant role in the regulation of cell fate by recruiting repression proteins or inhibiting the binding of transcription factors to DNA to regulate gene expression. Limb development is a well-established model for understanding cell fate decisions, and the formation of skeletal elements is coordinated through a sequence of events that control chondrogenesis spatiotemporally. It has been established that epigenetic control participates in cartilage maturation. However, further investigation is required to determine its role in the earliest stages of chondrocyte differentiation. This study investigates how the DNA methylation environment affects cell fate divergence during the early chondrogenic events. Our research has shown for the first time that inhibiting DNA methylation in interdigital tissue with 5-azacytidine results in the formation of an ectopic digit. This discovery suggested that DNA methylation dynamics could regulate the fate of cells between chondrogenesis and cell death during autopod development. Our in vitro findings indicate that DNA methylation at the early stages of chondrogenesis is integral in regulating condensation by controlling cell adhesion and proapoptotic genes. As a result, the dynamics of methylation and demethylation are crucial in governing chondrogenesis and cell death during different stages of limb chondrogenesis.


Assuntos
Diferenciação Celular , Condrócitos , Condrogênese , Metilação de DNA , Extremidades , Metilação de DNA/genética , Condrogênese/genética , Animais , Extremidades/embriologia , Diferenciação Celular/genética , Condrócitos/metabolismo , Condrócitos/citologia , Azacitidina/farmacologia , Regulação da Expressão Gênica no Desenvolvimento , Embrião de Galinha , Epigênese Genética , Apoptose/genética
8.
Development ; 149(9)2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35552394

RESUMO

In central nervous system vascular endothelial cells, signaling via the partially redundant ligands WNT7A and WNT7B requires two co-activator proteins, GPR124 and RECK. WNT7A and RECK have been shown previously to play a role in limb development, but the mechanism of RECK action in this context is unknown. The roles of WNT7B and GPR124 in limb development have not been investigated. Using combinations of conventional and/or conditional loss-of-function alleles for mouse Wnt7a, Wnt7b, Gpr124 and Reck, including a Reck allele that codes for a protein that is specifically defective in WNT7A/WNT7B signaling, we show that reductions in ligand and/or co-activator function synergize to cause reduced and dysmorphic limb bone growth. Two additional limb phenotypes - loss of distal Lmx1b expression and ectopic growth of nail-like structures - occur with reduced Wnt7a/Wnt7b gene copy number and, respectively, with Reck mutations and with combined Reck and Gpr124 mutations. A third limb phenotype - bleeding into a digit - occurs with the most severe combinations of Wnt7a/Wnt7b, Reck and Gpr124 mutations. These data imply that the WNT7A/WNT7B-FRIZZLED-LRP5/LRP6-GPR124-RECK signaling system functions as an integral unit in limb development.


Assuntos
Embrião de Mamíferos/metabolismo , Extremidades/embriologia , Proteínas Ligadas por GPI/metabolismo , Receptores Acoplados a Proteínas G , Proteínas Wnt , Animais , Sistema Nervoso Central/metabolismo , Células Endoteliais/metabolismo , Ligantes , Camundongos , Proteínas Proto-Oncogênicas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Proteínas Wnt/genética , Proteínas Wnt/metabolismo
9.
Development ; 149(5)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35274676

RESUMO

The 5'Hox genes play crucial roles in limb development and specify regions in the proximal-distal axis of limbs. However, there is no direct genetic evidence that Hox genes are essential for limb development in non-mammalian tetrapods or for limb regeneration. Here, we produced single to quadruple Hox13 paralog mutants using the CRISPR/Cas9 system in newts (Pleurodeles waltl), which have strong regenerative capacities, and also produced germline mutants. We show that Hox13 genes are essential for digit formation in development, as in mice. In addition, Hoxa13 has a predominant role in digit formation, unlike in mice. The predominance is probably due to the restricted expression pattern of Hoxd13 in limb buds and the strong dependence of Hoxd13 expression on Hoxa13. Finally, we demonstrate that Hox13 genes are also necessary for digit formation in limb regeneration. Our findings reveal that the general function of Hox13 genes is conserved between limb development and regeneration, and across taxa. The predominance of Hoxa13 function both in newt limbs and fish fins, but not in mouse limbs, suggests a potential contribution of Hoxa13 function in fin-to-limb transition.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio , Animais , Extremidades , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Botões de Extremidades/metabolismo , Camundongos , Salamandridae/genética , Salamandridae/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Dev Biol ; 493: 1-11, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36265686

RESUMO

Hedgehog (HH) signaling is a major driver of tissue patterning during embryonic development through the regulation of a multitude of cell behaviors including cell fate specification, proliferation, migration, and survival. HH ligands signal through the canonical receptor PTCH1 and three co-receptors, GAS1, CDON and BOC. While previous studies demonstrated an overlapping and collective requirement for these co-receptors in early HH-dependent processes, the early embryonic lethality of Gas1;Cdon;Boc mutants precluded an assessment of their collective contribution to later HH-dependent signaling events. Specifically, a collective role for these co-receptors during limb development has yet to be explored. Here, we investigate the combined contribution of these co-receptors to digit specification, limb patterning and long bone growth through limb-specific conditional deletion of Cdon in a Gas1;Boc null background. Combined deletion of Gas1, Cdon and Boc in the limb results in digit loss as well as defects in limb outgrowth and long bone patterning. Taken together, these data demonstrate that GAS1, CDON and BOC are collectively required for HH-dependent patterning and growth of the developing limb.


Assuntos
Moléculas de Adesão Celular , Proteínas Hedgehog , Receptores de Superfície Celular , Feminino , Gravidez , Proteínas de Transporte , Moléculas de Adesão Celular/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas Hedgehog/metabolismo , Receptores de Superfície Celular/metabolismo , Animais
11.
Development ; 148(23)2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34822715

RESUMO

SMAD4 regulates gene expression in response to BMP and TGFß signal transduction, and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we identify the SMAD4 target genes in mouse limb buds using an epitope-tagged Smad4 allele for ChIP-seq analysis in combination with transcription profiling. This analysis shows that SMAD4 predominantly mediates BMP signal transduction during early limb bud development. Unexpectedly, the expression of cholesterol biosynthesis enzymes is precociously downregulated and intracellular cholesterol levels are reduced in Smad4-deficient limb bud mesenchymal progenitors. Most importantly, our analysis reveals a predominant function of SMAD4 in upregulating target genes in the anterior limb bud mesenchyme. Analysis of differentially expressed genes shared between Smad4- and Shh-deficient limb buds corroborates this function of SMAD4 and also reveals the repressive effect of SMAD4 on posterior genes that are upregulated in response to SHH signaling. This analysis uncovers opposing trans-regulatory inputs from SHH- and SMAD4-mediated BMP signal transduction on anterior and posterior gene expression during the digit patterning and outgrowth in early limb buds.


Assuntos
Padronização Corporal , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Hedgehog/metabolismo , Botões de Extremidades/embriologia , Transdução de Sinais , Proteína Smad4/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog/genética , Membro Posterior/embriologia , Camundongos , Camundongos Transgênicos , Proteína Smad4/genética
12.
Bioessays ; 44(12): e2200139, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36251875

RESUMO

Hedgehog (HH) signaling is a conserved pathway that drives developmental growth and is essential for the formation of most organs. The expression of HH target genes is regulated by a dual switch mechanism where GLI proteins function as bifunctional transcriptional activators (in the presence of HH signaling) and transcriptional repressors (in the absence of HH signaling). This results in a tight control of GLI target gene expression during rapidly changing levels of pathway activity. It has long been presumed that GLI proteins also repress target genes prior to the initial expression of HH in a given tissue. This idea forms the basis for the limb bud pre-patterning model for regulating digit number. Recent findings indicate that GLI repressor proteins are indeed present prior to HH signaling but contrary to this model, GLI proteins are inert as they do not regulate transcriptional responses or enhancer chromatin modifications at this time. These findings suggest that GLI transcriptional repressor activity is not a default state as assumed, but is itself regulated in an unknown fashion. We discuss these findings and their implications for understanding pre-patterning, digit regulation, and HH-driven disease.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas Hedgehog , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Fatores de Transcrição/metabolismo , Transdução de Sinais/fisiologia , Expressão Gênica
13.
Int J Mol Sci ; 25(17)2024 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-39273297

RESUMO

Genetic variants in the zone of polarizing activity regulatory sequence (ZRS) that induce ectopic expression of the SHH gene have been associated with different ZRS-related phenotypes. We report the first patient with a de novo variant, c.423+4916 T>C, in ZRS (previously classified as a variant of uncertain significance) that causes tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome (THPTTS). A two-month-old male patient presented with bilateral preaxial polydactyly, triphalangeal thumb, and tibial agenesis and was heterozygous for the variant c.423+4916T>C (neither of his parents was a carrier). The findings obtained from the family study were sufficient to reclassify the variant from "uncertain significance" to "likely pathogenic" according to three criteria from the American College of Medical Genetics and Genomics guidelines, as follows: (1) absence of gnomAD, (2) confirmation of paternity and maternity, and (3) strong phenotype-genotype association. In ZRS-associated syndromes, a wide clinical spectrum has been observed, ranging from polydactyly to THPTTS; our patient has the most severe and rare phenotype. We did not perform functional assays. However, the c.423+4916T>C variant is flanked by three variants, which have been proven not only to cause the phenotype but also to increase the expression of SHH. Through all this data gathering, we consider the c.423+4916T>C variant to be causative of THPTTS.


Assuntos
Ectromelia , Deformidades Congênitas da Mão , Polegar , Humanos , Lactente , Masculino , Anormalidades Múltiplas/genética , Anormalidades Congênitas , Ectromelia/genética , Estudos de Associação Genética , Deformidades Congênitas da Mão/genética , Proteínas Hedgehog/genética , Disostose Mandibulofacial , Mutação , Fenótipo , Polidactilia/genética , Polegar/anormalidades , Tíbia/anormalidades , Dedos do Pé/anormalidades
14.
Int J Mol Sci ; 25(17)2024 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-39273445

RESUMO

Limb muscle is responsible for physical activities and myogenic cell migration during embryogenesis is indispensable for limb muscle formation. Maternal obesity (MO) impairs prenatal skeletal muscle development, but the effects of MO on myogenic cell migration remain to be examined. C57BL/6 mice embryos were collected at E13.5. The GeoMx DSP platform was used to customize five regions along myogenic cell migration routes (myotome, dorsal/ventral limb, limb stroma, limb tip), and data were analyzed by GeomxTools 3.6.0. A total of 2224 genes were down-regulated in the MO group. The GO enrichment analysis showed that MO inhibited migration-related biological processes. The signaling pathways guiding myogenic migration such as hepatocyte growth factor signaling, fibroblast growth factor signaling, Wnt signaling and GTPase signaling were down-regulated in the MO E13.5 limb tip. Correspondingly, the expression levels of genes involved in myogenic cell migration, such as Pax3, Gab1, Pxn, Tln2 and Arpc, were decreased in the MO group, especially in the dorsal and ventral sides of the limb. Additionally, myogenic differentiation-related genes were down-regulated in the MO limb. MO impedes myogenic cell migration and differentiation in the embryonic limb, providing an explanation for the impairment of fetal muscle development and offspring muscle function due to MO.


Assuntos
Diferenciação Celular , Movimento Celular , Desenvolvimento Muscular , Obesidade Materna , Animais , Movimento Celular/genética , Camundongos , Feminino , Desenvolvimento Muscular/genética , Diferenciação Celular/genética , Gravidez , Obesidade Materna/metabolismo , Obesidade Materna/genética , Camundongos Endogâmicos C57BL , Regulação da Expressão Gênica no Desenvolvimento , Transcriptoma , Desenvolvimento Embrionário/genética , Extremidades/embriologia , Perfilação da Expressão Gênica , Transdução de Sinais , Músculo Esquelético/metabolismo , Músculo Esquelético/embriologia
15.
Development ; 147(21)2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665241

RESUMO

Disruption of the minor spliceosome due to mutations in RNU4ATAC is linked to primordial dwarfism in microcephalic osteodysplastic primordial dwarfism type 1, Roifman syndrome, and Lowry-Wood syndrome. Similarly, primordial dwarfism in domesticated animals is linked to positive selection in minor spliceosome components. Despite being vital for limb development and size regulation, its role remains unexplored. Here, we disrupt minor spliceosome function in the developing mouse limb by ablating one of its essential components, U11 small nuclear RNA, which resulted in micromelia. Notably, earlier loss of U11 corresponded to increased severity. We find that limb size is reduced owing to elevated minor intron retention in minor intron-containing genes that regulate cell cycle. As a result, limb progenitor cells experience delayed prometaphase-to-metaphase transition and prolonged S-phase. Moreover, we observed death of rapidly dividing, distally located progenitors. Despite cell cycle defects and cell death, the spatial expression of key limb patterning genes was maintained. Overall, we show that the minor spliceosome is required for limb development via size control potentially shared in disease and domestication.


Assuntos
Nanismo/genética , Extremidades/embriologia , Retardo do Crescimento Fetal/genética , Microcefalia/genética , Osteocondrodisplasias/genética , RNA Nuclear Pequeno/metabolismo , Animais , Padronização Corporal/genética , Ciclo Celular/genética , Feminino , Membro Anterior/embriologia , Membro Anterior/ultraestrutura , Regulação da Expressão Gênica no Desenvolvimento , Membro Posterior/embriologia , Membro Posterior/ultraestrutura , Íntrons/genética , Masculino , Camundongos Endogâmicos C57BL , Mutação/genética , RNA Nuclear Pequeno/genética , Células-Tronco/metabolismo
16.
Development ; 147(19)2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-32907847

RESUMO

Pattern formation is influenced by transcriptional regulation as well as by morphogenetic mechanisms that shape organ primordia, although factors that link these processes remain under-appreciated. Here we show that, apart from their established transcriptional roles in pattern formation, IRX3/5 help to shape the limb bud primordium by promoting the separation and intercalation of dividing mesodermal cells. Surprisingly, IRX3/5 are required for appropriate cell cycle progression and chromatid segregation during mitosis, possibly in a nontranscriptional manner. IRX3/5 associate with, promote the abundance of, and share overlapping functions with co-regulators of cell division such as the cohesin subunits SMC1, SMC3, NIPBL and CUX1. The findings imply that IRX3/5 coordinate early limb bud morphogenesis with skeletal pattern formation.


Assuntos
Cromátides/metabolismo , Proteínas de Homeodomínio/metabolismo , Botões de Extremidades/embriologia , Botões de Extremidades/metabolismo , Fatores de Transcrição/metabolismo , Animais , Western Blotting , Segregação de Cromossomos/genética , Segregação de Cromossomos/fisiologia , Feminino , Imunofluorescência , Células HEK293 , Proteínas de Homeodomínio/genética , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Mitose/genética , Mitose/fisiologia , Gravidez , RNA-Seq , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/genética
17.
Proc Biol Sci ; 290(1990): 20221928, 2023 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-36629110

RESUMO

Bats have undergone one of the most drastic limb innovations in vertebrate history, associated with the evolution of powered flight. Knowledge of the genetic basis of limb organogenesis in bats has increased but little has been documented regarding the differences between limb organogenesis in bats and that of other vertebrates. We conducted embryological comparisons of the timelines of limb organogenesis in 24 bat species and 72 non-bat amniotes. In bats, the time invested for forelimb organogenesis has been considerably extended and the appearance timing of the forelimb ridge has been significantly accelerated, whereas the timing of the finger and first appearance of the claw development has been delayed, facilitating the enlargement of the manus. Furthermore, we discovered that bats initiate the development of their hindlimbs earlier than their forelimbs compared with other placentals. Bat neonates are known to be able to cling continuously with their well-developed foot to the maternal bodies or habitat substrates soon after birth. We suggest that this unique life history of neonates, which possibly coevolved with powered flight, has driven the accelerated development of the hindlimb and precocious foot.


Assuntos
Quirópteros , Animais , Recém-Nascido , Humanos , Vertebrados , Membro Anterior , Organogênese/genética , Membro Posterior , Eutérios , Voo Animal
18.
Proc Natl Acad Sci U S A ; 117(2): 1090-1096, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31896583

RESUMO

In the tetrapod limb, the digits (fingers or toes) are the elements most subject to morphological diversification in response to functional adaptations. However, despite their functional importance, the mechanisms controlling digit morphology remain poorly understood. Here we have focused on understanding the special morphology of the thumb (digit 1), the acquisition of which was an important adaptation of the human hand. To this end, we have studied the limbs of the Hoxa13 mouse mutant that specifically fail to form digit 1. We show that, consistent with the role of Hoxa13 in Hoxd transcriptional regulation, the expression of Hoxd13 in Hoxa13 mutant limbs does not extend into the presumptive digit 1 territory, which is therefore devoid of distal Hox transcripts, a circumstance that can explain its agenesis. The loss of Hoxd13 expression, exclusively in digit 1 territory, correlates with increased Gli3 repressor activity, a Hoxd negative regulator, resulting from increased Gli3 transcription that, in turn, is due to the release from the negative modulation exerted by Hox13 paralogs on Gli3 regulatory sequences. Our results indicate that Hoxa13 acts hierarchically to initiate the formation of digit 1 by reducing Gli3 transcription and by enabling expansion of the 5'Hoxd second expression phase, thereby establishing anterior-posterior asymmetry in the handplate. Our work uncovers a mutual antagonism between Gli3 and Hox13 paralogs that has important implications for Hox and Gli3 gene regulation in the context of development and evolution.


Assuntos
Extremidades/crescimento & desenvolvimento , Proteínas de Homeodomínio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fatores de Transcrição/metabolismo , Proteína Gli3 com Dedos de Zinco/metabolismo , Animais , Padronização Corporal , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Transcriptoma , Proteína Gli3 com Dedos de Zinco/genética
19.
Dev Dyn ; 251(9): 1423-1438, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34435397

RESUMO

BACKGROUND: Migrating muscle progenitors delaminate from the somite and subsequently form muscle tissue in distant anatomical regions such as the paired appendages, or limbs. In amniotes, this process requires a signaling cascade including the transcription factor paired box 3 (Pax3). RESULTS: In this study, we found that, unlike in mammals, pax3a/3b double mutant zebrafish develop near to normal appendicular muscle. By analyzing numerous mutant combinations of pax3a, pax3b and pax7a, and pax7b, we determined that there is a feedback system and a compensatory mechanism between Pax3 and Pax7 in this developmental process, even though Pax7 alone is not required for appendicular myogenesis. pax3a/3b/7a/7b quadruple mutant developed muscle-less pectoral fins. CONCLUSIONS: We found that Pax3 and Pax7 are redundantly required during appendicular myogenesis in zebrafish, where Pax7 is able to activate the same developmental programs as Pax3 in the premigratory progenitor cells.


Assuntos
Fatores de Transcrição Box Pareados , Peixe-Zebra , Animais , Mamíferos , Desenvolvimento Muscular/genética , Músculo Esquelético , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX7/genética , Fatores de Transcrição Box Pareados/genética , Peixe-Zebra/genética
20.
Dev Dyn ; 251(9): 1414-1422, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34811837

RESUMO

Seminal work from John Fallon's lab has illuminated how digit identity determination involves ongoing late regulation and occurs progressively during phalanx formation. Complementary genetic analyses in mice and several papers in this special issue have begun to flesh out how interdigit signaling accomplishes this, but major questions remain unaddressed, including how uncommitted progenitors from which phalanges arise are maintained, and what factors set limits on digit extension and phalanx number, particularly in mammals. This review summarizes what has been learned in the two decades since control of digit identity by late interdigit signals was first identified and what remains poorly understood, and will hopefully spark renewed interest in a process that is critical to evolutionary limb adaptations but nevertheless remains enigmatic.


Assuntos
Extremidades , Transdução de Sinais , Animais , Evolução Biológica , Mamíferos , Camundongos
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