SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning

Author:

Gamart Julie1,Barozzi Iros2ORCID,Laurent Frédéric1ORCID,Reinhardt Robert1,Martins Laurène Ramos1,Oberholzer Thomas1,Visel Axel234ORCID,Zeller Rolf1ORCID,Zuniga Aimée1ORCID

Affiliation:

1. Developmental Genetics, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland

2. Functional Genomics Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

3. US Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA

4. School of Natural Sciences, University of California, Merced, CA 95343, USA

Abstract

ABSTRACT SMAD4 regulates gene expression in response to BMP and TGFβ 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 Smad4- and 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.

Funder

Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung

European Research Council

National Institutes of Health

US Department of Energy

Universität Basel

Publisher

The Company of Biologists

Subject

Developmental Biology,Molecular Biology

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