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.

Grant Number: 5R21HD118147-02
NIH Institute/Center: NIH
Principal Investigator: Lindsey Barske