Reciprocal regulation of Shh trafficking and H₂O₂ levels via a noncanonical BOC-Rac1 pathway

Abstract

Among molecules that bridge environment, cell metabolism, and cell signaling, H2O2 recently appeared as an emerging but central player. Its level depends on cell metabolism and environment and was recently shown to play key roles during embryogenesis, contrasting with its long-established role in disease progression. We decided to explore whether the secreted morphogen Sonic hedgehog (Shh), known to be essential in a variety of biological processes ranging from embryonic development to adult tissue homeostasis and cancers, was part of these interactions. Here, we report that H2O2 levels control key steps of Shh delivery and that physiological in vivo modulation of H2O2 levels changes Shh distribution and tissue patterning. A feedback loop exists in which Shh trafficking controls H2O2 synthesis via a non-canonical BOC-Rac1 pathway, leading to cytoneme growth. Our findings reveal that Shh directly impacts its own distribution, thus providing a molecular explanation for the robustness of morphogenesis to both environmental insults and individual variability.

An early Shh-H2O2 feedback loop controls the progression of the regenerative program during adult zebrafish fin regeneration

“…Shh protects endometrial hyperplasial cells 32 , cortical neurons 33 and hippocampal cells 34 against oxidative stress. H2O2 levels control key steps of Shh delivery ex vivo and change the Shh distribution and tissue patterning during zebrafish development 35,36 . During zebrafish fin regeneration, injured nerves induce the production of large amounts of H2O2 through activation of the Shh pathway, providing an environment that promotes cell plasticity, progenitor recruitment and blastema formation 22,27 .…”