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 down-regulated and intracellular cholesterol levels are reduced in Smad4-deficient limb bud mesenchymal progenitors. Most importantly, our analysis reveals a predominant function of SMAD4 in up-regulating 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 up-regulated 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.
SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning
These authors contributed equally to this study.
Current address: Gene Regulation and Cardiac Development, Department of Biomedical Research, University of Bern, 3008 Bern, Switzerland
Current address: Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria
Current address: EMBL Heidelberg, 69117 Heidelberg, Germany
- Award Group:
- Funder(s): Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Award Id(s): 310030B_166685
- Funder(s):
- Award Group:
- Funder(s): European Research Council
- Award Id(s): INTEGRAL ERC-2015-AdG; Project ID 695032
- Funder(s):
- Award Group:
- Funder(s): Universität Basel
- Funder(s):
Currently Viewing Accepted Manuscript - Newer Version Available
- Split-screen
- Views Icon Views
- Open the PDF for in another window
-
Article Versions Icon
Versions
- Version of Record 03 December 2021
- Accepted Manuscript 25 November 2021
- Share Icon Share
-
Tools Icon
Tools
- Search Site
Julie Gamart, Iros Barozzi, Frédéric Laurent, Robert Reinhardt, Laurène Ramos Martins, Thomas Oberholzer, Axel Visel, Rolf Zeller, Aimée Zuniga; SMAD4 target genes are part of a transcriptional network that integrates the response to BMP and SHH signaling during early limb bud patterning. Development 2021; dev.200182. doi: https://doi.org/10.1242/dev.200182
Download citation file:
Advertisement
Call for papers: Uncovering Developmental Diversity
Development invites you to submit your latest research to our upcoming special issue: Uncovering Developmental Diversity. This issue will be coordinated by our academic Editor Cassandra Extavour (Harvard University, USA) alongside two Guest Editors: Liam Dolan (Gregor Mendel Institute of Molecular Plant Biology, Austria) and Karen Sears (University of California Los Angeles, USA).
Choose Development in 2024
In this Editorial, Development Editor-in-Chief James Briscoe and Executive Editor Katherine Brown explain how you support your community by publishing in Development and how the journal champions serious science, community connections and progressive publishing.
Journal Meeting: From Stem Cells to Human Development
Register now for the 2024 Development Journal Meeting From Stem Cells to Human Development. Early-bird registration deadline: 3 May. Abstract submission deadline: 21 June.
Pluripotency of a founding field: rebranding developmental biology
This collaborative Perspective, the result of a workshop held in 2023, proposes a set of community actions to increase the visibility of the developmental biology field. The authors make recommendations for new funding streams, frameworks for collaborations and mechanisms by which members of the community can promote themselves and their research.
Read & Publish Open Access publishing: what authors say
We have had great feedback from authors who have benefitted from our Read & Publish agreement with their institution and have been able to publish Open Access with us without paying an APC. Read what they had to say.