Journal
DEVELOPMENT
Volume 148, Issue 23, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.200182
Keywords
SMAD4; BMP; SHH; Limb development; Anterior; Mouse; ChIP-seq; RNA-seq; Cistrome
Categories
Funding
- Schweizerischer Nationalfonds zur Forderung der wissenschaftlichen Forschung grant [310030B_166685]
- European Research Council-2015-AdG Project INTEGRAL [695032]
- National Institutes of Health [R01HG003988, U54HG006997, UM1HG009421]
- US Department of Energy [DE-AC02-05CH11231]
- The Universitat Basel
- Swiss National Science Foundation (SNF) [310030B_166685] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [695032] Funding Source: European Research Council (ERC)
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SMAD4 regulates gene expression in early limb buds, primarily mediating BMP signal transduction and playing a crucial role in upregulating target genes in anterior limb bud mesenchyme, while also repressing posterior gene expression. This study reveals opposing trans-regulatory inputs from SHH- and SMAD4-mediated BMP signal transduction during digit patterning and outgrowth in early limb buds.
SMAD4 regulates gene expression in response to BMP and TGF beta signal transduction, and is required for diverse morphogenetic processes, but its target genes have remained largely elusive. Here, we identify the SMAD4 target genes in mouse limb buds using an epitope-tagged Smad4 allele for ChIP-seq analysis in combination with transcription profiling. This analysis shows that SMAD4 predominantly mediates BMP signal transduction during early limb bud development. Unexpectedly, the expression of cholesterol biosynthesis enzymes is precociously downregulated and intracellular cholesterol levels are reduced in Smad4-deficient limb bud mesenchymal progenitors. Most importantly, our analysis reveals a predominant function of SMAD4 in upregulating target genes in the anterior limb bud mesenchyme. Analysis of differentially expressed genes shared between Smad4and Shh-deficient limb buds corroborates this function of SMAD4 and also reveals the repressive effect of SMAD4 on posterior genes that are upregulated in response to SHH signaling. This analysis uncovers opposing trans-regulatory inputs from SHH- and SMAD4-mediated BMP signal transduction on anterior and posterior gene expression during the digit patterning and outgrowth in early limb buds.
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