1. Hox gene activity directs physical forces to differentially shape chick small and large intestinal epithelia.
- Author
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Gill, Hasreet K., Yin, Sifan, Nerurkar, Nandan L., Lawlor, John C., Lee, ChangHee, Huycke, Tyler R., Mahadevan, L., and Tabin, Clifford J.
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HOMEOBOX genes , *TRANSFORMING growth factors , *INTESTINAL mucosa , *SMOOTH muscle , *TRANSCRIPTION factors - 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. [Display omitted] • Mechanical properties define epithelial buckling in the developing chick intestine • HOXD13 promotes hindgut mechanics through increased mesenchymal TGF-β signaling • Hindgut and ectopic midgut HOXD13- expressing smooth muscle upregulates INHBA • Mesenchymal TGF-β activation tunes mechanics via extracellular matrix remodeling Gill et al. mechanistically link HOXD13 expression to morphogenesis of the chick hindgut epithelium. HOXD13 activity within smooth muscle induces INHBA expression, which causes adjacent mesenchymal cells to remodel extracellular matrix (ECM) in response to TGF-β upregulation, thus promoting the biomechanical parameters that define the hindgut morphological trajectory. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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