Distinctive functioning of STARD1 in the fetal Leydig cells compared to adult Leydig and adrenal cells. Impact of Hedgehog signaling via the primary cilium.

Abstract STARD1 stimulates cholesterol transfer to mitochondrial CYP11A1 for conversion to pregnenolone. A cholesterol-binding START domain is guided by an N-terminal domain in a cell selective manner. Fetal and adult Leydig cells (FLC, ALC) show distinct Stard1 regulation. sm- FISH microscopy, which resolves individual molecules of Stard1 mRNA, shows uniformly high basal expression in each FLC. In ALC, in vivo, and cultured MA-10 cells, basal Stard1 expression is minimal. PKA activates loci asynchronously, with delayed splicing/export of 3.5 kb mRNA to mitochondria. After 60 min, ALC transition to an integrated mRNA delivery to mitochondria that parallels FLC. Sertoli cells cooperate in Stard1 stimulation in FLC by delivering DHH to the primary cilium, where PTCH, SMO and cholesterol cooperate to release GLI3 to activate the Stard1 locus, probably by directing histone changes. ALC lack cilia. PKA primes ALC locus activation. FLC and ALC share similar SIK/CRTC/CREB regulation characterized for adrenal cells.