A mechano-chemical feedback via the extracellular matrix drives tissue elongation How do organs reliably

Akankshi  Munjal

How do organs reliably acquire the correct shape during development? To address this, we study the morphogenesis of semicircular canals in the zebrafish inner ear, a process driven by the initiation, elongation, and fusion of epithelial buds inside the fluid-filled embryonic otic vesicle. Our previous work showed that localized production of hyaluronic acid (HA) and its interaction with the HA-binding proteoglycan Versican generate osmotic swelling pressure that drives bud initiation. In this talk, I’ll present new, unpublished findings revealing a self-organizing mechano-chemical feedback loop that governs bud elongation. We find that the Yap mechanotransduction pathway patterns bud-forming cells in response to two mechanical cues: osmotic pressure generated by HA-Versican and attachment to the basement membrane. Using single-cell RNA-seq, we identified ccn1l1 as a Yap-responsive gene enriched in canal-forming cells. Quantitative in situ hybridization shows that while ccn1l1 is initially patterned independently of Yap, HA pressure significantly amplifies its expression via Yap during bud elongation. Functionally, ccn1l1 promotes further HA synthesis, creating a positive feedback loop: ccn1l1 drives HA production, and the resulting pressure activates Yap to amplify ccn1l1 in neighboring cells, recruiting them into the bud. Bud elongation is terminated upon bud fusion, which activates the mechanosensitive GPCR Gpr126. Gpr126 signaling via cAMP downregulates ccn1l1 expression and HA synthesis, breaking the feedback loop. These findings support a model in which mechanical forces and biochemical signaling interact to produce self-organized behaviors that drive tissue morphogenesis.