Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1

Wade, Christine, Brinas, Inigo, Welfare, Megan, Wicking, Carol and Farlie, Peter G. (2012) Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1. Developmental Biology, 370 1: 145-153. doi:10.1016/j.ydbio.2012.07.025

Author Wade, Christine
Brinas, Inigo
Welfare, Megan
Wicking, Carol
Farlie, Peter G.
Title Twist2 contributes to termination of limb bud outgrowth and patterning through direct regulation of Grem1
Journal name Developmental Biology   Check publisher's open access policy
ISSN 0012-1606
Publication date 2012-10-01
Sub-type Article (original research)
DOI 10.1016/j.ydbio.2012.07.025
Open Access Status Not Open Access
Volume 370
Issue 1
Start page 145
End page 153
Total pages 9
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Language eng
Abstract Twist1 has been demonstrated to play critical roles in the early development of neural crest and mesodermally derived tissues including the limb. Twist2 has been less well characterised but its relatively late onset of expression suggests specific roles in the development of a number of organs. Expression of Twist2 within the developing limbs begins after formation of the limb bud and persists within the peripheral mesenchyme until digital rays condense. We have used RCAS-mediated overexpression in chick to investigate the function of Twist2 in limb development. Viral misexpression following injection into the lateral plate mesoderm results in a spectrum of hypoplastic limb phenotypes. These include generalized shortening of the entire limb, fusion of the autopod skeletal elements, loss of individual digits or distal truncation resulting in complete loss of the autopod. These phenotypes appear to result from a premature termination of limb outgrowth and manifest as defective growth in both the proximal-distal and anterior-posterior axes. In situ hybridisation analysis demonstrates that many components of the Shh/Grem1/Fgf regulatory loop that controls early limb growth and patterning are downregulated by Twist2 overexpression. Grem1 has a complementary expression pattern to Twist2 within the limb primordia and co-expression of both Grem1 and Twist2 results in a rescue of the Twist2 overexpression phenotype. We demonstrate that Twist proteins directly repress Grem1 expression via a regulatory element downstream of the open reading frame. These data indicate that Twist2 regulates early limb morphogenesis through a role in terminating the Shh/Grem1/Fgf autoregulatory loop.
Keyword Twist2
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online: 1 August 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
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