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Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis

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....

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Autores principales: Firulli, Beth A., Milliar, Hannah, Toolan, Kevin P., Harkin, Jade, Fuchs, Robyn K., Robling, Alex G., Firulli, Anthony B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536869/
https://www.ncbi.nlm.nih.gov/pubmed/28576769
http://dx.doi.org/10.1242/dev.149963
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author Firulli, Beth A.
Milliar, Hannah
Toolan, Kevin P.
Harkin, Jade
Fuchs, Robyn K.
Robling, Alex G.
Firulli, Anthony B.
author_facet Firulli, Beth A.
Milliar, Hannah
Toolan, Kevin P.
Harkin, Jade
Fuchs, Robyn K.
Robling, Alex G.
Firulli, Anthony B.
author_sort Firulli, Beth A.
collection PubMed
description 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.
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spelling pubmed-55368692017-08-22 Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis Firulli, Beth A. Milliar, Hannah Toolan, Kevin P. Harkin, Jade Fuchs, Robyn K. Robling, Alex G. Firulli, Anthony B. Development Research Article 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. The Company of Biologists Ltd 2017-07-01 /pmc/articles/PMC5536869/ /pubmed/28576769 http://dx.doi.org/10.1242/dev.149963 Text en © 2017. Published by The Company of Biologists Ltd http://creativecommons.org/licenses/by/3.0This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Firulli, Beth A.
Milliar, Hannah
Toolan, Kevin P.
Harkin, Jade
Fuchs, Robyn K.
Robling, Alex G.
Firulli, Anthony B.
Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
title Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
title_full Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
title_fullStr Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
title_full_unstemmed Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
title_short Defective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
title_sort defective hand1 phosphoregulation uncovers essential roles for hand1 in limb morphogenesis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536869/
https://www.ncbi.nlm.nih.gov/pubmed/28576769
http://dx.doi.org/10.1242/dev.149963
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