Neural Crest Regulation of Embryonic Calcium Uptake

PROJECT SUMMARY Calcium is the most stringently regulated ion in multicellular organisms and an essential component of cellular signaling pathways. A major influx of calcium from the external environment is required to initiate bone mineralization in vertebrate embryos. Though the major transcellular routes of calcium entry at embryonic stages have been determined for both mammalian and aquatic species, how the amount of calcium uptake is calibrated remains uncertain. The Barske lab has identified an unexpected regulatory role for the transcription factor Sox10 in acquiring calcium for larval bone mineralization in zebrafish. sox10 mutants are known to lack or be severely deficient in many neural crest-derived cell lineages, including glia, pigment, and sympathetic, sensory, and enteric neurons. The lab’s preliminary studies revealed that in the absence of sox10, a kidney-associated gland makes excess amounts of an anti-hypercalcemic hormone, stanniocalcin, which blocks most calcium uptake and thus bone mineralization. sox10+ crest-derived cells were observed in close contact with this endocrine gland in control but not mutant fish. Neither Sox10 nor neural crest have previously been linked to embryonic mineral regulation, marking this a notable advance for the field. The objectives of this proposal are to determine the identity of the sox10+ crest-derived lineage that interacts with the endocrine gland as well as the molecular and cellular pathways linking the two. The hypothesis tested in Aim 1 is that these sox10+ cells are the precursors of the sympathetic nerves that will regulate function of this gland in adults. If supported, this would have the broader implication that cells destined to become an organ’s sympathetic ganglia may make contact early and begin regulating organ function while still in the progenitor state, presumably through non-neuronal mechanisms. The hypothesis tested in Aim 2 is that the regulatory interaction between crest and gland involves deranged signaling of the Calcium Sensing Receptor, a key factor for adult calcium homeostasis that may also be involved in calibrating embryonic calcium uptake. Completion of this aim will add an embryonic dimension to the abundant literature on adult calcium homeostasis and bone mineralization, emphasizing that hormone production must be kept in balance even at early stages when calcium content is climbing rapidly. This is relevant for human gestation as well: developmental endocrine disruptions analogous to those of this fish model could interfere with calcium uptake through the placenta, even with maternal dietary calcium supplementation, and contribute to low bone mineral density at birth.