A self-limiting mechanotransduction feedback loop ensures robust organ formation.

Area of Science:

• Developmental Biology
• Mechanobiology
• Molecular Biology

Background:

• Organ morphogenesis relies on mechanotransduction feedback loops to translate mechanical forces into gene expression.
• The integration of these feedback loops with developmental programs for robust outcomes is not well understood.

Purpose of the Study:

• To investigate the role of Yap mechanotransduction in a self-limiting positive feedback loop during zebrafish semicircular canal formation.
• To elucidate how this feedback loop integrates with developmental programs to ensure robust organogenesis.

Main Methods:

• Analysis of zebrafish otic epithelium development, focusing on bud initiation, extension, and fusion.
• Investigating the spatial activation patterns of Yap and its target gene, ccn1l1, in response to extracellular matrix (ECM) swelling.
• Examining the role of PKA-CREB signaling and the adhesion GPCR, gpr126, in loop termination.

Main Results:

• Yap activation, driven by hyaluronan-rich ECM swelling, induces ccn1l1, promoting ECM expansion and bud extension.
• The Yap-ccn1l1 feedback loop confers developmental robustness, allowing canal formation to persist despite graded reductions in ccn1l1.
• PKA-CREB signaling, activated by gpr126 during bud fusion, suppresses ccn1l1, terminating the feedback loop.

Conclusions:

• Mechanotransduction feedback loops, like the one involving Yap, are crucial for robust organ morphogenesis.
• Integrated feedback loops with inherent termination mechanisms provide precise developmental control by linking mechanical cues to morphogenetic outcomes.