Inhibitory SMAD6 interferes with BMP-dependent generation of muscle progenitor cells and perturbs proximodistal pattern of murine limb muscles

Asfour, H. ORCID: https://orcid.org/0000-0002-4107-3981, Hirsinger, E. ORCID: https://orcid.org/0000-0002-5256-7741, Rouco, R. ORCID: https://orcid.org/0000-0002-0657-0704, Zarrouki, F. ORCID: https://orcid.org/0000-0003-0905-9036, Hayashi, S. ORCID: https://orcid.org/0000-0001-5553-7698, Swist, S. ORCID: https://orcid.org/0000-0002-1269-2177, Braun, T. ORCID: https://orcid.org/0000-0002-6165-4804, Patel, K. ORCID: https://orcid.org/0000-0002-7131-749X, Relaix, F. ORCID: https://orcid.org/0000-0003-1270-1472, Andrey, G. ORCID: https://orcid.org/0000-0002-0911-4907, Stricker, S. ORCID: https://orcid.org/0000-0002-7174-5363, Duprez, D. ORCID: https://orcid.org/0000-0003-0248-7417, Stantzou, A. ORCID: https://orcid.org/0000-0002-4903-6384 and Amthor, H. ORCID: https://orcid.org/0000-0003-1008-719X (2023) Inhibitory SMAD6 interferes with BMP-dependent generation of muscle progenitor cells and perturbs proximodistal pattern of murine limb muscles. Development, 150 (11). dev201504. ISSN 1477-9129 doi: 10.1242/dev.201504

Abstract/Summary

The mechanism of pattern formation during limb muscle development remains poorly understood. The canonical view holds that naïve limb muscle progenitor cells (MPCs) invade a pre-established pattern of muscle connective tissue, thereby forming individual muscles. Here we show that early murine embryonic limb MPCs highly accumulate pSMAD1/5/9, demonstrating active signaling of bone morphogenetic proteins (BMP) in these cells. Overexpression of inhibitory SMAD6 in limb MPCs abrogated BMP signaling, impaired their migration and proliferation, and accelerated myogenic lineage progression. Fewer primary myofibers developed, causing an aberrant proximodistal muscle pattern. Patterning was not disturbed when SMAD6 was overexpressed in differentiated muscle, implying that the proximodistal muscle pattern depends on BMP-mediated expansion of MPCs prior to their differentiation. We show that limb MPCs differentially express Hox genes, and Hox-expressing MPCs displayed active BMP signaling. SMAD6 overexpression caused loss of HOXA11 in early limb MPCs. In conclusion, our data show that BMP signaling controls expansion of embryonic limb MPC as a prerequisite for establishing the proximodistal muscle pattern, a process that involves expression of Hox genes.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/112118
Identification Number/DOI	10.1242/dev.201504
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Uncontrolled Keywords	Developmental Biology, Molecular Biology
Publisher	The Company of Biologists
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