Wunen(s) help navigate Primordial Germ Cells by attenuating Hedgehog signaling

Directed cell migration is a vital process that depends on the combined activities of attractive and repulsive cues. As it is essential for normal development, the precise identity of guidance signals and the underlying molecular and cellular mechanisms is being rigorously investigated. In a Drosophila embryo, PGC migration is orchestrated by non-cell autonomous repulsive and attractive cues, controlled by Wunen(s) - Wunen and Wunen2 and, HMGCoA-reductase (Hmgcr), respectively. Hedgehog (Hh), a PGC attractant, is potentiated by Hmgcr. We demonstrate that Wunen(s) employ both nonautonomous and autonomous modes to inhibit Hh signaling. Consistently, in embryos maternally compromised for wunen, mesodermal cells and PGCs accumulate excess Hh, leading to precocious clumping of the PGCs. This behaviour is reminiscent of PGC-specific loss of patched (ptc) - the Hh receptor and an antagonist of Smoothened (Smo), a G protein-coupled receptor (GPCR), involved in Hh signal transduction. Consistently, Wunen(s) inhibit membrane localization of Smo. Conversely, simultaneous overexpression of wunen mitigates PGC scattering induced by ectopic hmgcr expression. Finally, unbiased lipidomics of embryonic extracts after maternal knockdown of wunen confirms disruptions in lipid metabolism. We discuss the mechanistic underpinnings of Wunen(s) involvement in repressing Hh signalling to engineer PGC migration.