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bioRxiv · 10.1101/2023.11.09.564741

An extra-genital cell population contributes to urethra closure during mouse penis development

Amato, C. M.·Xu, X.·Yao, H. H.-C.
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Abstract

Hypospadias, or incomplete closure of the urethra along the penis, is the second most common birth defect in the United States. We discovered a population of extra- genital mesenchymal cells that are essential for proper penile urethra closure in mouse embryos. This extra-genital population first appeared in the mesenchyme posterior to the hindlimb of the fetus after the onset of penis formation. These extra-genital cells, which transiently express a lineage marker Nr5a1, migrated centrally and colonized the penis bilateral to the urethra epithelium. Removal of the Nr5a1+ extra-genital cells, using a cell-type specific ablation model, resulted in severe hypospadias. The absence of extra-genital cells had the most significant impacts on another mesenchymal cells, the peri-urethra that were immediately adjacent to the Nr5a1+ extra-genital cells. Single cell mRNA sequencing revealed that the extra-genital cells extensively interact with the peri-urethra, particularly through Neuregulin 1, an epidermal Growth Factor (EGF) ligand. Disruption of Neuregulin 1 signaling in the ex-vivo slice culture system led to failure of urethra closure, recapitulating the phenotypes of extra-genital cell ablation. These results demonstrate that the Nr5a1+ extra-genital mesenchymal cells from outside of the fetal penis are indispensable for urethra closure through their interaction with the peri-urethra mesenchymal cells. This discovery provides a new entry point to understand the biology of penis formation and potential causes of hypospadias in humans.

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Amato, C. M., Xu, X., Yao, H. H.-C.. 2023-11-11. An extra-genital cell population contributes to urethra closure during mouse penis development. https://doi.org/10.1101/2023.11.09.564741

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