Abstract
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.
Highlights
The vertebrate limb is an evolutionarily dynamic structure that has adapted broadly to fit the intended functional role, be it running, climbing, flying or swimming
Hand1 appears to play no necessary role in limb morphogenesis when deleted with Prrx1Cre, we reasoned that its participation in regulating the bHLH dimer pool within the cells of the developing limb bud could result in disruption of limb morphogenesis, as suggested from observations comparing Hand1 deletion within the neural crest versus disruption of Hand1 dimerization (Barbosa et al, 2007; Firulli et al, 2014)
Limb morphogenesis is a complex process that allows for significant variation in structure leading to diversity within a population that is tested by natural selection
Summary
The vertebrate limb is an evolutionarily dynamic structure that has adapted broadly to fit the intended functional role, be it running, climbing, flying or swimming. 18% of children born with congenital limb defects die by 6 years of age due to additional associated defects in more vital organs. The mechanisms of limb outgrowth and patterning are well defined, a better understanding of the underlying relationships between the gene. Received 30 January 2017; Accepted 18 May 2017 programs causative of proximal limb deformities could facilitate a better understanding of how these same programs interplay in other organ systems resulting in defects that lead to lethality
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