BMP–Smad1/9 signaling plays a critical role in regulating zebrafish PGC proliferation

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Abstract
The germ cell fate in zebrafish is determined by germ plasm, whereas mammalian germ cell fate is induced by bone morphogenetic protein (BMP) signaling. It remains elusive whether BMP signaling is implicated in zebrafish germ cell development. Here, we demonstrate that BMP–Smad1/9 signaling plays a critical role in zebrafish primordial germ cell (PGC) maintenance rather than fate determination. BMP inhibition or smad1/9 knockdown reduces PGC numbers. Furthermore, we generated PGC-specific smad1/9 knockouts using a transgenic approach with PGC-specifically expressed Cas9 and ubiquitously expressed guide RNAs. Smad1/9 deficiency in PGCs leads to impaired PGC proliferation and increased apoptosis, consequently reducing PGC numbers. Transcriptome analysis revealed unchanged PGC-specific gene expression, but a marked upregulation of DNA damage response-related genes, which is validated by ectopic ATR–pChk1 activation in PGCs and PGC restoring by ATR inhibition. Collectively, these findings underscore conserved but functionally distinct roles of BMP signaling in vertebrate PGC development.

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