Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
| Autor: | Anthony B. Firulli, Alexander G. Robling, Beth A. Firulli, Jade Harkin, Hannah Milliar, Robyn K. Fuchs, Kevin P. Toolan |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Mouse Limb Buds Transcription Genetic Gene Dosage Morphogenesis Hand1 Mesoderm Mice 03 medical and health sciences Limb bud bHLH GLI3 Basic Helix-Loop-Helix Transcription Factors Transcriptional regulation Animals Limb development Hedgehog Proteins Phosphorylation Molecular Biology Alleles Body Patterning Homeodomain Proteins Regulation of gene expression Genetics Cell Death Integrases biology Gene Expression Regulation Developmental Cell biology body regions Phenotype 030104 developmental biology Mutation biology.protein Female HAND2 Dimerization Transcription Limb morphogenesis Gene Deletion Research Article Signal Transduction Developmental Biology |
| Zdroj: | Development (Cambridge, England) |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.149963 |
| Popis: | The morphogenesis of the vertebrate limbs is a complex process in which cell signaling and transcriptional regulation coordinate diverse structural adaptations in diverse species. In this study, we examine the consequences of altering Hand1 dimer choice regulation within developing vertebrate limbs. Although Hand1 deletion via the limb-specific Prrx1-Cre reveals a non-essential role for Hand1 in mouse limb morphogenesis, altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, results in a severe truncation of proximal-anterior limb elements. Molecular analysis reveals a non-cell-autonomous mechanism that causes widespread cell death within the embryonic limb bud. In addition, we observe changes in proximal-anterior gene regulation, including a reduction in the expression of Irx3, Irx5, Gli3 and Alx4, all of which are upregulated in Hand2 limb conditional knockouts. A reduction of Hand2 and Shh gene dosage improves the integrity of anterior limb structures, validating the importance of the Twist-family bHLH dimer pool in limb morphogenesis. Summary: Altering Hand1 phosphoregulation, and consequently Hand1 dimerization affinities, results in a severe truncation of anterior-proximal limb elements in mice. |
| Databáze: | OpenAIRE |
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