HCF-1:OGT-mediated transcriptional repression of WDR91 coordinates neuronal differentiation and CNS regeneration
Neuronal differentiation and CNS regeneration require tightly regulated intracellular homeostasis, yet the transcriptional mechanisms controlling components of the endolysosomal system during these processes remain poorly defined. Here, we identify WDR91 as a regulator of neuronal differentiation and injury-induced CNS regeneration and uncover its regulation by the HCF-1:OGT axis. WDR91 expression is dynamically induced during neuronal differentiation and following CNS injury in adult zebrafish, while WDR91 depletion disrupts autophagic progression, neuronal differentiation, and regenerative responses. Mechanistically, HCF-1 directly occupies the Wdr91 promoter, while depletion of HCF-1 or inhibition of OGT increases Wdr91 expression, indicating transcriptional repression of Wdr91 by the HCF-1:OGT regulatory axis. Notably, simultaneous depletion of Hcfc1 and Wdr91 suppresses the neuronal differentiation defects observed following depletion of either factor alone, supporting a functional genetic relationship between HCF-1 and WDR91. Consistent with this relationship, loss of Hcfc1 and Wdr91 produces convergent transcriptomic signatures involving neuronal development and synaptic pathways. Together, our findings identify the HCF-1:OGT-WDR91 regulatory axis as an important determinant of neuronal differentiation and CNS regeneration and reveal WDR91 as a transcriptionally regulated component of the cellular machinery required for neuronal homeostasis
Neuronal differentiation and CNS regeneration require tightly regulated intracellular homeostasis, yet the transcriptional mechanisms controlling components of the endolysosomal system during these processes remain poorly defined. Here, we identify WDR91 as a regulator of neuronal differentiation and injury-induced CNS regeneration and uncover its regulation by the HCF-1:OGT axis. WDR91 expression is dynamically induced during neuronal differentiation and following CNS injury in adult zebrafish, while WDR91 depletion disrupts autophagic progression, neuronal differentiation, and regenerative responses. Mechanistically, HCF-1 directly occupies the Wdr91 promoter, while depletion of HCF-1 or inhibition of OGT increases Wdr91 expression, indicating transcriptional repression of Wdr91 by the HCF-1:OGT regulatory axis. Notably, simultaneous depletion of Hcfc1 and Wdr91 suppresses the neuronal differentiation defects observed following depletion of either factor alone, supporting a functional genetic relationship between HCF-1 and WDR91. Consistent with this relationship, loss of Hcfc1 and Wdr91 produces convergent transcriptomic signatures involving neuronal development and synaptic pathways. Together, our findings identify the HCF-1:OGT-WDR91 regulatory axis as an important determinant of neuronal differentiation and CNS regeneration and reveal WDR91 as a transcriptionally regulated component of the cellular machinery required for neuronal homeostasis