Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs

Dollé, Pascal; Dierich, Andrée; LeMeur, Marianne; Schimmang, Thomas; Schuhbaur, Brigitte; Chambon, Pierre; Duboule, Denis

doi:10.1016/0092-8674(93)90378-4

Cited by 427 publications

(286 citation statements)

References 42 publications

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“…Hox genes has been established by their homology to Drosophila genes of known developmental significance (McGinnis and Krumlauf, 19921, by their suggestive embryonic expression patterns (Holland and Hogan, 1988), and by both dominant gain of function (Wolgemuth et al, 1989;Kessel et al, 1990;Kaur et al, 1992;McLain et al, 1992;Jegalian and De Robertis, 1992;Pollock et al, 1992;Lufkin et al, 1992;Charite et al, 1994) and recessive loss of function (Chisaka and Capecchi, 1991;Lufkin et al, 1991;Chisaka et al, 1992;Mouellic et al, 1992;Ramirez-Solis et al, 1993;Dolle et al, 1993;Small and Potter, 1993) mutational analyses in mice.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, detailed Hox codes have now been defined for the determination of rhombomere identity in the developing hindbrain (Keynes and Krumlauf, 1994). Nevertheless, aspects of some mutant phenotypes have been difficult to interpret in terms of this model (Dolle et al, 1993;Small and Potter, 1993;Davis and Capecchi, 1994), suggesting that it may not universally apply.…”

Section: Introductionmentioning

confidence: 99%

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Gsh‐1: A novel murine homeobox gene expressed in the central nervous system

Valerius

Stock

et al. 1995

Developmental Dynamics

103

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We report the characterization of Gsh-1, a novel murine homeobox gene. Northern blot analysis revealed a transcript of approximately 2 kb in sue present at embryonic days 10.5, 11.5, and 12.5 of development. The cDNA sequence encoded a proline rich motif, a polyalanine tract, and a homeodomain with strong homology to those encoded by the clustered Hox genes. The Gsh-1 expression pattern was determined for days E8.5 to E13.5 by whole mount and serial section in situ hybridizations. Gsh-1 transcription was restricted to the central nervous system. Expression is present in the neural tube and hindbrain as two continuous, bilaterally symmetrical stripes within neural epithelial tissue. In the mesencephalon, expression is seen as a band across the most anterior portion. There is also diencephalon expression in the anlagen of the thalamus and the hypothalamus as well as in the optic stalk, optic recess, and the ganglionic eminence. Moreover, through the use of fusion proteins containing the Gsh-I homeodomain, we have determined the consensus DNA binding site of the Gsh-1 homeoprotein to be GCT/cA/,ATTAG/A. 0 1995 Wiley-Liss, Inc.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gsh‐1: A novel murine homeobox gene expressed in the central nervous system

Valerius

Stock

et al. 1995

Developmental Dynamics

103

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“…This is particularly true of 5Ј HoxA and HoxD genes, which are involved in limb patterning (reviewed in references 49 and 65). The inactivation of the Hoxd13 gene in mice, for instance, causes a phenotype resulting from defects in the proliferation and/or condensation of limb mesenchymal cells (11,14).Hox proteins have been shown to act as transcription factors, which are thought to regulate sets of target genes by binding to specific DNA sequences within the transcriptional regulatory regions of these (7,33,38,43,50,51,61,62). Recent findings, however, have hinted at a possible additional function for this family of DNA-binding proteins.…”

mentioning

confidence: 99%

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

Salsi¹,

Ferrari²,

Ferraresi

et al. 2009

Molecular and Cellular Biology

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HOX DNA-binding proteins control patterning during development by regulating processes such as cell aggregation and proliferation. Recently, a possible involvement of HOX proteins in replication origin activity was suggested by results showing that a number of HOX proteins interact with the DNA replication licensing regulator geminin and bind a characterized human origin of replication. The functional significance of these observations, however, remained unclear. We show that HOXD13, HOXD11, and HOXA13 bind in vivo all characterized human replication origins tested. We furthermore show that HOXD13 interacts with the CDC6 loading factor, promotes pre-replication complex (pre-RC) proteins assembly at origins, and stimulates DNA synthesis in an in vivo replication assay. HOXD13 expression in cultured cells accelerates DNA synthesis initiation in correlation with the earlier pre-RC recruitment onto origins during G 1 phase. Geminin, which interacts with HOXD13 as well, blocks HOXD13-mediated assembly of pre-RC proteins and inhibits HOXD13-induced DNA replication. Our results uncover a function for Hox proteins in the regulation of replication origin activity and reveal an unforeseen role for the inhibition of HOX protein activity by geminin in the context of replication origin licensing.Hox proteins belong to the large family of homeodomaincontaining DNA-binding proteins. During embryonic development they control cell fates, eventually leading to the generation of different regional identities along the primary body and limb axes (17,35). Genetic analyses, including loss-and gainof-function experiments, showed that vertebrate Hox genes modulate morphogenetic processes by controlling crucial aspects such as cell proliferation and aggregation (16). This is particularly true of 5Ј HoxA and HoxD genes, which are involved in limb patterning (reviewed in references 49 and 65). The inactivation of the Hoxd13 gene in mice, for instance, causes a phenotype resulting from defects in the proliferation and/or condensation of limb mesenchymal cells (11,14).Hox proteins have been shown to act as transcription factors, which are thought to regulate sets of target genes by binding to specific DNA sequences within the transcriptional regulatory regions of these (7,33,38,43,50,51,61,62). Recent findings, however, have hinted at a possible additional function for this family of DNA-binding proteins. Hox proteins have been found to associate with the DNA replication licensing regulator geminin (39), and a number of them have been shown to bind the human LaminB2 and other origins of replication, suggesting their possible role in origin definition and/or assembly of the replication machinery (9,13,20). The functional significance of these observations, however, remained elusive.Origins of replication are poorly defined in metazoa. A consensus sequence appears not to be required for replication initiation in human cells, and only a few origins where replication initiates from a localized site in each cell cycle have been well characterize...

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“…The collective results support the hypothesis of a dual role for the Hox proteins in the developing skeleton: patterning of elements as well as control of their growth (Capecchi, 1996;Kappen, 1998;Yueh et al, 1998) While there is ample experimental evidence for a crucial function of Hox genes in skeletal patterning, it is still unclear how Hox transcription factors actually control patterning and growth. A simple model assumes that the collective local balance of Hox genes controls skeletogenic cell proliferation (Davis and Capecchi, 1994;Dolle et al, 1993;Duboule, 1995;Fromental-Ramain et al, 1996a;Fromental-Ramain et al, 1996b;Rancourt et al, 1995;Yueh et al, 1998). The control of rates of cell proliferation could be achieved either through transcriptional regulation, or through interactions with specific cell cycle proteins.…”

Section: Regionalization Along the Anterior-posterior Axis: Hox Genesmentioning

confidence: 99%

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

Kappen

Neubüser

Balling

et al. 2007

Birth Defects Research Pt B

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Skeletal variations are common in humans, and potentially are caused by genetic as well as environmental factors. We here review molecular principles in skeletal development to develop a knowledge base of possible alterations that could explain variations in skeletal element number, shape or size. Environmental agents that induce variations, such as teratogens, likely interact with the molecular pathways that regulate skeletal development. Birth Defects Res (Part B), 80:425–450, 2007. © 2007 Wiley‐Liss, Inc.

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Disruption of the Hoxd-13 gene induces localized heterochrony leading to mice with neotenic limbs

Cited by 427 publications

References 42 publications

Gsh‐1: A novel murine homeobox gene expressed in the central nervous system

Gsh‐1: A novel murine homeobox gene expressed in the central nervous system

HOXD13 Binds DNA Replication Origins To Promote Origin Licensing and Is Inhibited by Geminin

Molecular basis for skeletal variation: insights from developmental genetic studies in mice

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