Identifying genes affecting gonad development is essential to understand the mechanisms causing Variants/Differences in Sex Development. Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients. We show that Cv-c, the Drosophila ortholog of DLC3, is also required to maintain testis integrity during fly development. We found that Cv-c and human DLC3 can perform the same function in fly embryos, as flies with wild type but not mutated DLC3 rescue gonadal dysgenesis, suggesting a functional conservation. Expression of different Cv-c protein variants demonstrated that the StART domain mediates the Cv-c function in the male gonad, independently from the GAP domain activity. This work demonstrates a role for DLC3/Cv-c in male gonadogenesis and highlights a novel StART-mediated function required for gonadal mesoderm-germ cell interaction during testis development.

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Background: The identification of genes affecting gonad development is essential to understand the mechanisms causing Variations/Differences in Sex Development. Recently, a DLC3 mutation was associated with male gonadal dysgenesis in 46,XY DSD patients.Methods: We have studied the requirement of cv-c, the Drosophila ortholog of DLC3, for Drosophila gonad development as well as the functional capacity of DLC3 human variants to rescue cv-c gonad defects. We show that Cv-c is required to maintain testis integrity during fly development.Results: We find that Cv-c and human DLC3 can perform the same function in fly embryos, as flies carrying wild type but not patient DLC3 variations can rescue gonadal dysgenesis, suggesting a functional conservation. Expression of different Cv-c protein variants demonstrate that the StART domain mediates Cv-c's function in the male gonad independently from the GAP domain's activity.Conclusions: This work demonstrates a role for DLC3/Cv-c in male gonadogenesis and highlights a novel StART domain mediated function required to organize the gonadal mesoderm and maintain its interaction with the germ cells during testis development.Funding: María de Maeztu Unit excellence grants MDM-2016-0687 and CEX-2020-001088-M. Ministerio de Ciencia e Innovación grant PID2019-104656GB-I00 cofunded by the European Regional Development Fund (FEDER). Swiss National Science Foundation (PP00P3_194807). Swiss National Supercomputing Centre under project ID s1132. European Research Council under the European Union's Horizon 2020 research and innovation program (grant agreement no. 803952). Swiss National Science Foundation's Grant 320030-184807.Swiss National Science Foundation (grant number SCOPES IZ73Z0_152347/1) and National Academy of Sciences of Ukraine, project 'Molecular-Genetic Mechanisms of Human Disorders of Sexual Development' [0121U110054].