title: Calcium sensing receptor absence delays postnatal brain development via direct and indirect mechanisms.
abstract: Calcium sensing receptor (CaSR) is implicated in the establishment of neural connections and myelin formation. However, its contribution to brain development remains unclear. We addressed this issue by analyzing brain phenotype in postnatal CaSR null mice, a model of human neonatal severe hyperparathyroidism. One- and 2-week-old CaSR null mice exhibited decreased brain weight and size with a developmental delay in expression of proliferating cell nuclear antigen. Neuronal and glial differentiation markers, neuronal specific nuclear protein, glial fibrillary acidic protein, and myelin basic protein, were also decreased compared with age-matched wild-type littermates. Moreover, deletion of the parathyroid hormone gene that corrects hyperparathyroidism, hypercalcemia, hypophosphatemia, and whole-body growth retardation normalized brain cell proliferation, but not differentiation, in CaSR null mice. Cultured neural stem cells (NSCs) derived from the subventricular zones of CaSR null neonatal mice exhibited normal proliferation capacity but decreased differentiation capacity, compared with wild-type controls. These results demonstrate that direct effects of CaSR absence impair NSC differentiation, while secondary effects of parathyroid hormone-related endocrine abnormalities impair NSC proliferation, both of which contribute to delayed brain development in CaSR null newborn mice.
authors.affiliation: Department of Anatomy, Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Xiu-Ling
authors.initials: XL
authors.lastname: Liu
authors.forename: Yu-Shan
authors.initials: YS
authors.lastname: Lu
authors.forename: Jun-Ying
authors.initials: JY
authors.lastname: Gao
authors.forename: Charles
authors.initials: C
authors.lastname: Marshall
authors.forename: Ming
authors.initials: M
authors.lastname: Xiao
authors.forename: Deng-Shun
authors.initials: DS
authors.lastname: Miao
authors.forename: Andrew
authors.initials: A
authors.lastname: Karaplis
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: Jiong
authors.initials: J
authors.lastname: Ding
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000002:abnormalities / Q000254:growth & development* / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006934:Hypercalcemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D006961:Hyperparathyroidism / Q000150:complications / Q000378:metabolism / Q000473:pathology; D017674:Hypophosphatemia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009024:Morphogenesis / Q000187:drug effects; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010281:Parathyroid Hormone / Q000172:deficiency / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000172:deficiency* / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D002118:Calcium
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