HoxGene Expression in Limbs: Colinearity by Opposite Regulatory Controls
Open accessAbstract
Genes of the HoxD complex have a crucial role in the morphogenesis of vertebrate limbs. During development, their functional domains are colinear with their genomic positions within the HoxD cluster such that Hoxd13 and Hoxd12 are necessary for digit development, whereas Hoxd11 and Hoxd10 are involved in making forearms. Mutational analyses of these genes have demonstrated their importance and illustrated the requirement for a precise control of their expression during early limb morphogenesis. To study the nature of this control, we have scanned the posterior part of the HoxD complex with a targeted reporter transgene and analyzed the response of this foreign promoter to limb regulatory influences. The results suggest that this regulation is achieved through the opposite effects of two enhancer elements which would compete with each other for interacting with nearby-located promoters. The physical position of a given gene within this genomic interval of opposite regulations might thus determine its final expression pattern. This model provides a conceptual link between the morphology of the future limb and the genetic organization of the Hox gene cluster, a translation of a genomic context into a morphogenetic topology.
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A counteracting locus control region from beyond the 5' end represses posterior hox genes in anterior cells of the early limb bud, allowing their expression only in posterior limb bud cells.
“the posterior hox genes are repressed by a counteracting locus control region operating from beyond the 5' end of the complex in the anterior cells of the early limb bud, allowing expression of these genes only in the posterior limb bud cells.”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Herault et al., 1999
The Discussion (page unavailable) describes the element 5′ of HoxD as a digit enhancer, not a repressor of anterior limb-bud expression. Its proposed counteracting controls govern expression in digits versus forearm along the proximodistal axis; the paper does not describe a 5′ locus control region restricting posterior Hox genes to posterior limb-bud cells. (LLM, conf=0.85)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredEarly hoxd expression in the tetrapod limb bud is controlled not only by local enhancers but also by distant regulatory regions outside the hox gene clusters.
“early expression in the tetrapod limb bud is controlled not only by local enhancers but also by distant regulatory regions located outside the hox gene clusters.”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Herault et al., 1999
The Introduction (page unavailable) describes a distant enhancer, likely upstream of the HoxD complex, that drives expression in the distal digit domain. But the Discussion (page unavailable) concerns late limb expression and says nearby gene-specific elements may not significantly affect it. The paper therefore does not establish the claimed combination of local enhancers and distant regions controlling early limb-bud expression. (LLM, conf=0.86)
Experimental — accuracy not yet measuredA 3' regulatory region causes progressive expression of first anterior then middle hox genes in the limb bud region that will give rise to the forearm.
“One of these operates from the 3' (anterior) end of the cluster and causes the progressive expression of first anterior and then middle hox genes in the limb bud region that will give rise to the forearm.”
From Evolution of Gene Regulatory Networks Controlling Body Plan Development (2011) · cites this paper as Herault et al., 1999
The Introduction (page unavailable) describes early colinear activation, with Hoxd9 expressed before Hoxd10, and identifies a presumptive forearm expression domain. The reporter results (Fig. 2 section, page unavailable) associate more 3′ positions with forearm expression. But the Discussion says evidence for a separate forearm regulatory element is less compelling and offers alternative explanations, so the claim overstates a 3′ region as the established cause of that progression. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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- Authors
- Hérault, Y., Beckers, J., Gérard, M., & Duboule, D.
- Affiliations
- University of Geneva (CH)
- Corresponding author
- Duboule, Denis
- Venue
- Developmental Biology
- Publisher
- Elsevier BV
- Published
- 1999-04
- Volume
- 208
- Issue
- 1
- Pages
- 157-165
- ISSN
- 0012-1606 (ISSN-L)
- OpenAlex
- W2031498265
- Cited by
- 56
- References
- 26
- Citations by year
- 2024: 1 · 2021: 1 · 2016: 1 · 2015: 1 · 2013: 1 · 2012: 3
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Biology (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- Fonds National de la Recherche Luxembourg
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Keywords
- Hox genes, HoxD cluster, limb development, colinearity, transcriptional regulation, digit development, forelimb development, HOXD13, Hoxd11, HOXD10, reporter transgenes, gene expression patterning
- MeSH terms
- Animals, Enhancer Elements, Genetic, Extremities, Embryonic and Fetal Development, Genes, Homeobox, Morphogenesis, Phosphoglycerate Kinase, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, In Situ Hybridization, Homeodomain Proteins, Gene Expression Regulation, Developmental, Transgenes, Zebrafish Proteins, Mice
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