<i>Tbx4</i>is not required for hindlimb identity or post-bud hindlimb outgrowth

Naiche, L.A.; Papaioannou, Virginia E.

doi:10.1242/dev.02712

Cited by 76 publications

(99 citation statements)

References 46 publications

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“…Both studies reach identical conclusions: Tbx4 and Tbx5 are required during the initial phase of limb initiation but are dispensable for continued limb outgrowth (Hasson et al, 2007;Naiche and Papaioannou, 2007) (Fig. 2B).…”

Section: Tbx4 and Tbx5 Have Temporally Distinct Roles During Limb Devsupporting

confidence: 55%

Regulation of limb bud initiation and limb‐type morphology

Duboc¹,

Logan²

2011

Developmental Dynamics

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While the paired forelimb and hindlimb buds of vertebrates are initially morphologically homogeneous, as the limb progenitors differentiate, each individual tissue element attains a characteristic limb-type morphology that ultimately defines the constitution of the forelimb or hindlimb. This review focuses on contemporary understanding of the regulation of limb bud initiation and formation of limb-type specific morphologies and how these regulatory mechanisms evolved in vertebrates. We also attempt to clarify the definition of the terms limb-type identity and limb-type morphology that have frequently been used interchangeably. Over the last decade, three genes, Tbx4, Tbx5, and Pitx1, have been extensively studied for their roles in limb initiation and determining limb-type morphologies. The role of Tbx4 and Tbx5 in limb initiation is clearly established. However, their putative role in the generation of limb-type morphologies remains controversial. In contrast, all evidence supports a function for Pitx1 in determination of hindlimb morphologies.

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Section: Tbx4 and Tbx5 Have Temporally Distinct Roles During Limb Devsupporting

confidence: 55%

Regulation of limb bud initiation and limb‐type morphology

Duboc¹,

Logan²

2011

Developmental Dynamics

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“…In mice, however, it has been suggested that these two T-box genes initiate limb bud development by inducing Fgf10 in the mesenchyme, but are not involved in establishing limb identity (Naiche and Papaioannou, 2003;Minguillon et al, 2005;Naiche and Papaioannou, 2007). The molecular mechanisms of forelimb and hindlimb specification are not completely understood.…”

Section: Resultsmentioning

confidence: 99%

Dynamic gene expression of Lin-28 during embryonic development in mouse and chicken

Yokoyama

Hashimoto

Shimizu

et al. 2008

Gene Expression Patterns

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The Caenorhabditis elegans heterochronic gene lin-28 regulates developmental timing in the nematode trunk. We report the dynamic expression patterns of Lin-28 homologues in mouse and chick embryos. Whole mount in situ hybridization revealed specific and intriguing expression patterns of Lin-28 in the developing mouse and chick limb bud. Mouse Lin-28 expression was detected in both the fore-limb and hindlimb at E9.5, but disappeared from the forelimb at E10.5, and finally from the forelimb and hindlimb at E11.5. Chicken Lin-28, which was first detected in the limb primordium at stage 15/16, was also downregulated as the stage proceeded. The amino acid sequences of mouse and chicken Lin-28 genes are highly conserved and the similar expression patterns of Lin-28 during limb development in mouse and chicken suggest that this heterochronic gene is also conserved during vertebrate limb development. KeywordsHeterochronic gene; Whole mount in situ hybridization; Mouse; Chick; Limb bud; Lin-28; MicroRNAs; Developmental timing; Dynamic expression; Embryo Results and discussionEmbryonic development is tightly regulated by spatio-temporal gene expression; however, systems regulating developmental timing are largely unknown. A series of mutagenesis studies using the nematode Caenorhabditis elegans as a model have identified a cluster of genes, the so-called "heterochronic genes," which is expressed at the specific period of time during embryogenesis and play a critical role in determining the relative timing of developmental events (Ambros and Horvitz, 1984;Lee et al., 1993). Among these heterochronic genes, * Corresponding author. Address: Department of Systems Biomedicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, Japan. Tel/fax: +81 3 3417 2498., E-mail address: asahara@nch.go.jp (H. Asahara). Publisher's Disclaimer: This article was published in an Elsevier journal. The attached copy is furnished to the author for non-commercial research and education use, including for instruction at the author's institution, sharing with colleagues and providing to institution administration. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. To further examine the spatio-temporal expression patterns of Lin-28 in developing embryos, we performed whole mount in situ hybridization using mouse and chicken embryos at different developmental stages.Although Lin-28 was ubiquitously expressed throughout the mouse embryo at E9.5 (Fig. 1a, a′), strong expression was observed in the most distal mesenchyme adjacent to the apical ectodermal ridge (AER) of both forelimb and hindlimb buds (Fig. 1b, b′, white arrow). Interestingly, at E10.5, the expression of Lin-28 in forelimb almost disappeared, and expression was restricted to the hindlimb and more caudal trunk at the hindlimb level ( Fig. 1c-e). In a ...

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“…22 TBX4 is a known transcriptional target of PITX1 26,27 and is required for normal hindlimb development, [28][29][30][31] further supporting a role for the PITX1-TBX4 developmental pathway in talipes equinovarus etiology. Furthermore, PITX1 and TBX4 are two genes that are specifically expressed in the hindlimb compared with the forelimb, providing an explanation for the selective limb phenotype.…”

Section: Introductionmentioning

confidence: 88%

“…10 Interestingly, several genes located within the talipes equinovarus CNVs are specifically expressed in the hindlimb compared with the forelimb or known to be involved in early embryonic patterning. PITX1 and TBX4 are transcription factors that are essential for normal lower limb development 17,28,29,51 and CNVs involving each are associated with talipes equinovarus. 18,22,52 Although we identified recurrent duplications of chromosome 17q23 involving TBX4 in this report, reciprocal deletions have also been associated with talipes equinovarus.…”

Section: Copy Number Analysis In Talipes Equinovarusmentioning

confidence: 99%

Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development

et al. 2012

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Talipes equinovarus is one of the most common congenital musculoskeletal anomalies and has a worldwide incidence of 1 in 1000 births. A genetic predisposition to talipes equinovarus is evidenced by the high concordance rate in twin studies and the increased risk to first-degree relatives. Despite the frequency of isolated talipes equinovarus and the strong evidence of a genetic basis for the disorder, few causative genes have been identified. To identify rare and/or recurrent copy number variants, we performed a genome-wide screen for deletions and duplications in 413 isolated talipes equinovarus patients using the Affymetrix 6.0 array. Segregation analysis within families and gene expression in mouse E12.5 limb buds were used to determine the significance of copy number variants. We identified 74 rare, gene-containing copy number variants that were present in talipes equinovarus probands and not present in 759 controls or in the Database of Genomic Variants. The overall frequency of copy number variants was similar between talipes equinovarus patients compared with controls. Twelve rare copy number variants segregate with talipes equinovarus in multiplex pedigrees, and contain the developmentally expressed transcription factors and transcriptional regulators PITX1, TBX4, HOXC13, UTX, CHD (chromodomain protein)1, and RIPPLY2. Although our results do not support a major role for recurrent copy number variations in the etiology of isolated talipes equinovarus, they do suggest a role for genes involved in early embryonic patterning in some families that can now be tested with large-scale sequencing methods. INTRODUCTIONIsolated talipes equinovarus, also called clubfoot, is one of the most common serious congenital birth defects with an estimated birth prevalence of 1 per 1000 live births. 1 Talipes equinovarus consists of malalignment of the bones and joints of the foot and ankle, and is distinguished from positional foot anomalies because it is rigid and not passively correctable (Figure 1). Approximately 20% of talipes equinovarus cases are associated with chromosomal abnormalities, or known genetic syndromes 2,3 and it is a common component of several neurological disorders, including distal arthrogryposis, myotonic dystrophy, and myelomeningocele. Despite the frequency of talipes equinovarus in neurological disorders, no consistent neuromuscular abnormalities have been identified in isolated talipes equinovarus patients using muscle biopsy or electrophysiological examinations. [4][5][6][7] Most cases of clubfeet (80%) occur as isolated birth defects and are considered idiopathic. 8 Approximately 25% of patients with isolated talipes equinovarus report a family history of talipes equinovarus, suggesting a genetic basis for this disorder. 9 Twin studies also support a role for genetic factors, as identical twins have a 33% concordance rate for talipes

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Tbx4is not required for hindlimb identity or post-bud hindlimb outgrowth

Cited by 76 publications

References 46 publications

Regulation of limb bud initiation and limb‐type morphology

Regulation of limb bud initiation and limb‐type morphology

Dynamic gene expression of Lin-28 during embryonic development in mouse and chicken

Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development

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