Developing gut in mice undergoes rapid elongation during late embryogenesis, yet significantly slows down after birth. The precise regulatory mechanism of this dynamic morphogenetic process remains unknown. By utilizing single-cell RNA-sequencing analysis, we show that YAP activity in intestinal fibroblasts is the major molecular contributor to gut elongation. To determine how mesenchymal YAP activity is controlled, we identified canonical sarcolemma membrane-associated protein (SLMAP) as its critical regulator during mouse embryonic gut morphogenesis. Deleting Slmap in gut mesenchyme impairs YAP activity, leading to a short gut and a significant decrease in intestinal epithelial cell proliferation. Mechanistically, SLMAP activates YAP by directly regulating MST3 kinase. Physiologically, MST3 levels prominently increase over the developmental time, reaching their peak on postnatal day (P)14, when gut elongation in mice slows down. Depleting Mst3 in mesenchyme results in increased gut length at P14 accompanied by enhanced YAP activity. Importantly, a short gut phenotype in mesenchyme-specific Slmap mutant mice is partially compensated for by concomitant deletion of mesenchymal Mst3. Taken together, our findings demonstrate that SLMAP interacts with MST3 kinase to regulate the mesenchymal YAP activity that governs dynamic gut elongation across embryonic and postnatal development.

Keywords:
Gut elongation, Mesenchyme, Slmap, Mst3, Yap
Subjects:
Cell biology, Development and disease, Growth control, Signalling, Stem cells

Author contributions

Conceptualization: Y.P., Z.Y.; Data curation: Y.P., S.W., X.W., H.Z., S.D., M.Z., L.H.; Formal analysis: Y.P.; Funding acquisition: Z.Y.; Investigation: Y.P.; Methodology: Y.P.; Project administration: Z.Y.; Resources: Z.Y.; Software: W.Y.; Supervision: Z.Y.; Validation: Y.P.; Visualization: Y.P.; Writing – original draft: Y.P.; Writing – review & editing: M.V.P., J.S., C.L., L.Y., Z.Y.

Funding

This work was supported by the National Natural Science Foundation of China (82025006, 82230017 and 82341224 to Z.Y.; 82000498 and 82270588 to C. L.; 32200562 to L.Y.; and 12090052 and U24A2014 to J.S.), the National Key Research and Development Program of China (2022YFA1104001 and 2021YFF1000603 to Z.Y.; and 2022YFC3602102 and 2022YFD1300403 to C.L.), the Pinduoduo-China Agricultural University Research Fund (PC2023A02006 to Z.Y.) and the 2115 Talent Development Program of China Agricultural University.

Data and resource availability

The 3′-scRNA-seq datasets have been deposited in GEO under the accession number GSE277051. All generic and custom R, Python and MATLAB scripts are available on reasonable request. The RNA-Seq data have been deposited in GEO under the accession numbers GSE276611 and GSE276668.

Special Issue

This article is part of the Special Issue ‘Lifelong Development: the Maintenance, Regeneration and Plasticity of Tissues’, edited by Meritxell Huch and MansiSrivastava. See related articles at https://journals.biologists.com/dev/issue/152/20.

© 2025. Published by The Company of Biologists
2025
https://www.biologists.com/user-licence-1-2/
You do not currently have access to this content.