Biology subjects

Harsh, S.

Publications and source records attributed to Harsh, S..

3 recordsLinked to original sources

bioRxiv2025

The pioneer factor Zelda induces male-to-female somatic sex reversal in adult tissues

Somatic sex identity must be maintained throughout adulthood for tissue function. Adult somatic stem cells in the Drosophila testis (i.e., CySCs) lacking the transcription factor Chinmo are reprogrammed to their ovarian counterparts by induction of female-specific TraF, but this is not mechanistically understood. Pioneer factors play central roles in direct reprogramming, and many upregulated genes in chinmo-/- CySCs contain binding sites for the pioneer factor Zelda (Zld). microRNAs repress zld mRNA in wild type CySCs, but they are downregulated after Chinmo loss, allowing for zld mRNA translation. Zld depletion from chinmo-/- CySCs suppresses feminization, and ectopic Zld induces TraF and feminizes wild-type CySCs. qkr58E-2 and ecdysone receptor (EcR), direct Zld targets in the embryo, are female-biased in adult gonads and upregulated in chinmo-/- CySCs. The RNA-binding protein Qkr58E-2 produces TraF, while EcR promotes female-biased gene expression. Ectopic Zld feminizes adult male adipose tissue, demonstrating that Zld can instruct female and override male identity in adult XY tissues. HighlightsO_LIzld mRNA is repressed by microRNAs in XY somatic gonadal cells C_LIO_LIZld is upregulated in and required for sex reversal of XY chinmo-/- cells C_LIO_LIZld induces Qkr58E-2 and EcR, which cause TraF and female-biased transcription C_LIO_LIZld feminizes XY adipose cells by inducing TraF and downregulating Chinmo C_LI

developmental biology↗

bioRxiv2024

Conversion of somatic sex identity in the testis induces female-specific cellular behaviors in the soma and early oocyte specification in the germline

Establishment and maintenance of cellular sex identity is essential for reproduction. Critically, the sex identity of somatic and germline cells must correspond for sperm or oocytes to be produced, with mismatched identity causing infertility in all organisms from flies to humans. In the Drosophila testis, Chronologically inappropriate morphogenesis (Chinmo) is required for maintenance of adult male somatic identity. Loss of chinmo leads to progressive feminization of the male soma, including adoption of female-specific cell morphologies, tissue organization and gene expression. However, the degree to which this feminized soma in the male engages female-specific cellular behaviors or influences the associated XY germline is unknown. Using extended live imaging, we have visualized the process of male-to-female somatic sex conversion upon chinmo loss of function. We find that feminized soma in the testis engage cell behaviors characteristic of ovarian follicle cells (FCs), including female-specific incomplete cytokinesis, as early as one day of chinmo inhibition. In the ovary, FCs collectively migrate around the underlying germ cells to establish the elongated shape of the oocyte. Surprisingly, we find that FC-like soma in chinmo-depleted testes also engage this female-specific collective cell migration. Critically, migration of FC-like cells in the testis has the same molecular requirements as FC migration in the ovary. Depletion of the basement membrane protein Perlecan or adhesion protein Ecadherin significantly disrupts rotational migration in both the ovary and chinmo-depleted testes. Finally, we find that feminized soma non-autonomously alters sex identity of the associated XY germ cells, inducing expression of a protein required for early oocyte specification. Taken together, our work reveals a dramatic transformation of somatic cell behavior during the process of sex conversion and provides a powerful model to study soma-derived induction of oocyte identity.

developmental biology↗

bioRxiv2021

A Serpin27A-dependent Toll Signaling Underlies Host Genetics of Cancer Resistance in Drosophila

Cancer resistance varies amongst individuals, although its host genetic underpinnings remain largely elusive. Remissions of sarcomas were first reported following repeated injections of patients with mixtures of killed bacteria--Coleys toxins--a phenomenon, which was subsequently causally traced to induction of innate immunity. Here we reveal remission of Drosophila epithelial neoplasms by genetically triggered host innate immunity via Toll signaling. These neoplasms display capacities to receive and, in rare instances, induce Toll signaling. A tumor-induced and progressive Toll signaling, however, did not culminate in tumor suppression. By contrast, Drosophila hosts heterozygous for spn27A1 mutation, which constitutively produce activated Toll ligand, SpzAct, displayed comprehensive tumor remission via Toll-induced, NF-{kappa}B-mediated, tumor cell death. Our results reveal a novel node of host genetic cancer resistance via serpin-dependent Toll signaling.

cancer biology↗