2. Academic Validation
  3. Hox gene activity directs physical forces to differentially shape chick small and large intestinal epithelia

Hox gene activity directs physical forces to differentially shape chick small and large intestinal epithelia

  • Dev Cell. 2024 Aug 1:S1534-5807(24)00449-0. doi: 10.1016/j.devcel.2024.07.012.
Hasreet K Gill 1,  Sifan Yin 2,  Nandan L Nerurkar 3,  John C Lawlor 1,  ChangHee Lee 1,  Tyler R Huycke 4,  L Mahadevan 5,  Clifford J Tabin 6
Affiliations

Affiliations

  • 1 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA.
  • 3 The Fu Foundation School of Engineering and Applied Science, Columbia University, New York, NY 10027, USA.
  • 4 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 5 Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Physics, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: lm@seas.harvard.edu.
  • 6 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: tabin@genetics.med.harvard.edu.
PMID: 39116876 DOI: 10.1016/j.devcel.2024.07.012
Abstract

Hox transcription factors play crucial roles in organizing developmental patterning across metazoa, but how these factors trigger regional morphogenesis has largely remained a mystery. In the developing gut, Hox genes help demarcate identities of intestinal subregions early in embryogenesis, which ultimately leads to their specialization in both form and function. Although the midgut forms villi, the hindgut develops sulci that resolve into heterogeneous outgrowths. Combining mechanical measurements of the embryonic chick intestine and mathematical modeling, we demonstrate that the posterior Hox gene HOXD13 regulates biophysical phenomena that shape the hindgut lumen. We further show that HOXD13 acts through the transforming growth factor β (TGF-β) pathway to thicken, stiffen, and promote isotropic growth of the subepithelial mesenchyme-together, these features lead to hindgut-specific surface buckling. TGF-β, in turn, promotes collagen deposition to affect mesenchymal geometry and growth. We thus identify a cascade of events downstream of positional identity that direct posterior intestinal morphogenesis.

Keywords

Hox genes; TGF-β pathway; gut; mechanical forces; modeling; morphogenesis.

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