Open AccessDefective Hand1 phosphoregulation uncovers essential roles for Hand1 in limb morphogenesis
Author(s) -
Beth A. Firulli,
Hannah Milliar,
Kevin P. Toolan,
Jade Harkin,
Robyn K. Fuchs,
Alex G. Robling
Publication year - 2017
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.15
H-Index - 36
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.149963
Subject(s) - biology , limb development , morphogenesis , gli3 , limb bud , microbiology and biotechnology , apical ectodermal ridge , embryonic stem cell , conditional gene knockout , vertebrate , compartment (ship) , anatomy , gene , regulation of gene expression , genetics , embryo , transcription factor , mesoderm , repressor , phenotype , oceanography , geology
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.