Biology subjects

JOSHI, R.

Publications and source records attributed to JOSHI, R..

3 recordsLinked to original sources

bioRxiv2026

Serine/Threonine phosphatase PP1 is a regulator of Notch signalling.

Cell diversity generation is cardinal to the development of the functional central nervous system. The Notch pathway plays an important role in neurogenesis, spanning cell fate determination, cell death, and neural stem cell (NSC) competence switching, and is therefore highly regulated within cells. While the phosphorylation-based regulation of the pathway and its associated kinases is known, few phosphatases have been identified to counterbalance these regulations. Protein Phosphatase 1 is a member of a Serine/Threonine family of phosphatases responsible for a large majority of dephosphorylation events in the cell. In this study, we identify PP1- and its regulatory subunit, PNUTS, as novel regulators of the Notch signalling pathway during Drosophila neurogenesis. We show that PP1-87B/PNUTS positively regulate Notch signalling by dephosphorylating a highly conserved Serine residue in Su(H) to restore its DNA binding activity and thereby activating Notch downstream targets during neurogenesis. This facilitates the execution of two distinct physiological events, NSC apoptosis and competence switching, in different regions of the Drosophila CNS. We find that this regulation of the Notch pathway is also extendable to another cellular context, epithelial wing disc tissue, and critically relies on the phosphatase activity of PP1. Given that we can rescue the Notch-dependent depletion phenotypes of PP1- using its human ortholog, we believe this regulation is likely to be conserved across species during development.

developmental biology↗

bioRxiv2025

SWI/SNF ATPase Brahma and Notch signaling collaborate with CBP/p300 to regulate neural stem cell apoptosis in Drosophila larval central nervous system.

SWI-SNF ATPase Brahma and Notch signalling are known to interact during development, but how this interaction is executed at the molecular level is not fully understood. We have investigated the molecular mechanism of Brm-Notch interaction in the context of Hox-dependent neural stem cell (NSC) apoptosis in the developing Central Nervous System (CNS) of Drosophila. Our results suggest a multi-tier regulation of NSC apoptosis by Brahma, first by regulating the expression of Drosophila CBP/p300 (Nejire) and the molecular triggers of cell death (Hox, bHLH factor Grainyhead, and Notch signalling pathway). The second mode of regulation is by direct binding of Brahma to the apoptotic enhancer and its collaboration with Notch signalling pathway to regulate the RHG family of apoptotic genes, grim and reaper. Our data support a model where, upon activation of Notch signaling, Brahma and CSL-Su(H)/Mastermind complex recruit CBP/p300 onto the apoptotic enhancer. This increases the H3K27ac marks on the nucleosomes to open up the chromatin and facilitate apoptotic gene transcription in Abd-B and Grh dependent manner.

developmental biology↗

bioRxiv2025

Drosophila grainyhead gene and its neuroblast-specific enhancers show epigenetic synchrony in the cells of central nervous system.

Enhancers are the epicentres of tissue-specific gene regulation. In this study, we have used the central nervous system (CNS) specific expression of the Drosophila grainyhead (grh) gene to make a case for deleting the enhancers in a sensitised background of other enhancer deletion, to functionally validate their role in tissue-specific gene regulation. We identified novel enhancers for grh and subsequently deleted two of them, to establish their collective importance in regulating grh expression in CNS. This showed that grh relies on multiple enhancers for its robust expression in neural stem cells (NSCs), with different combinations of enhancers playing a critical role in regulating its expression in various subset of these cells. We also found that these enhancers and the grh gene show epigenetic synchrony across the three cell types (NSCs, intermediate progenitors and neurons) of the developing CNS; and grh is not transcribed in intermediate progenitor cells, which inherits the Grh protein from the NSCs. We propose that this could be a general mechanism for regulating the expression of cell fate determinant protein in intermediate progenitor cells. Lastly, our results underline that enhancer redundancy results in phenotypic robustness in grh gene expression, which seems to be a consequence of the cumulative activity of multiple enhancers.

developmental biology↗