Abstract
Heterozygous variants in SOX10 cause congenital syndromes affecting pigmentation, digestion, hearing, and neural development, primarily attributable to failed differentiation or loss of non-skeletal neural crest derivatives. We report here an additional, previously undescribed requirement for Sox10 in bone mineralization. Neither crest- nor mesoderm-derived bones initiate mineralization on time in zebrafish sox10 mutants, despite normal osteoblast differentiation and matrix production. Mutants are deficient in the Trpv6+ ionocytes that take up calcium from the environment, resulting in severe calcium deficiency. As these ionocytes derive from ectoderm, not crest, we hypothesized that the primary defect resides in a separate organ that systemically regulates ionocyte numbers. RNA sequencing revealed significantly elevated stanniocalcin (Stc1a), an anti-hypercalcemic hormone, in sox10 mutants. Stc1a inhibits calcium uptake in fish by repressing trpv6 expression and Trpv6+ ionocyte proliferation. Epistasis assays confirm excess Stc1a as the proximate cause of the calcium deficit. The pronephros-derived glands that synthesize Stc1a interact with sox10+ cells, but these cells are missing in mutants. We conclude that sox10+ crest-derived cells non-autonomously limit Stc1a production to allow the inaugural wave of calcium uptake necessary to initiate bone mineralization.