Mechanism Of Hippo Signaling Regulating Drosophila Intestine Homeostasis And The Role Of Nerfin-1 In Drosophila Optic Lobe Development

Stem cells possess the unique properties of self-renewal and differentiation potency,therefore playing critical roles in the development,homeostasis maintenance and organ regeneration.Recent sdudies have shown that the conserved Hippo signaling pathway is a universal governor in organ development,tissue regeneration,stem cell maintenance,and tumorigenesis.The central role of Hippo signaling in stem cell biology makes it a focal point for therapeutic manipulation in anticancer therapies and organ regeneration.To gain better understanding o the mechanism of Hippo signaling in regulating stem cell proliferation,we focus our study on cell proliferation and fate determination using Drosophila as a model system.Tissue homeostasis and regeneration in the Drosophila midgut is regulated by a diverse array of signaling pathways including the Hippo pathway.It is known that Hippo signaling restricts intestinal stem cell(ISC)proliferation by sequestering the transcription co-factor Yorkie(Yki)in the cytoplasm,which required for rapid ISC proliferation under injury-induced regeneration.Nonetheless,the mechanism of Hippomediated midgut homeostasis and whether canonical Hippo signaling is involved in ISC basal proliferation remain less well-defined.Here we identify Lola as a transcription factor acting downstream of Hippo signaling to restrict ISC proliferation in a Yki-independent manner.Not only that Lola interacts with and is stabilized by the Hippo signaling pathway core kinase Warts(Wts),Lola rescues the enhanced ISC proliferation upon Wts depletion via suppressing Dref and Skp A expression.Our findings reveal that Lola is a non-canonical Hippo signaling component in regulating midgut homeostasis,providing insights on the mechanism of tissue maintenance and intestinal function.The Drosophila larval central nervous system constists of central brain,ventral nerve cord and optic lobe.Neuroblast(NB)undergoes asymmetrical division to keep self-renew and generate differentiated neurons or glia.Mechanisms of preventing neuron dedifferentiation remain elusive,especially in the optic lobe.Here,we show that the zinc-finger transcription factor Nerfin-1 binds with Hippo signaling downstream transcription factor Scallopeda.Nerfin-1 expresses in early-stage medulla neurons and is essential for maintaining their differentiation.Depletion of Nerfin-1 induces activation of Notch signaling,which promotes neuron-to-NB reversion.Repressing Notch signaling largely rescues dedifferentiation in loss-of-Nerfin-1 clones.Thus,we conclude that Nerfin-1 represses Notch signaling activity in medulla neurons and prevents them from dedifferentiation.Taken together,our work uncover a novel Wts-Lola-Skp A/Dref signaling axis in regulating Drosophila midgut homeostasis and restricting ISC proliferation.We also demonstrate the function of Nerfin-1 in medulla neurons preventing them from dedifferentiation by suppressing Notch activity.Our work on Lola and Nerfin-1 in Drosophila adult midgut and larval central nervous systems uncover another layer of complexity in the Hippo signaling pathway transcriptional regulatory mechanism in stem cell proliferation.