title: Absence of PTHrP nuclear localization and carboxyl terminus sequences leads to abnormal brain development and function.
abstract: We assessed whether the nuclear localization sequences (NLS) and C terminus of parathyroid hormone-related protein (PTHrP) play critical roles in brain development and function. We used histology, immunohistochemistry, histomorphometry, Western blots and electrophysiological recordings to compare the proliferation and differentiation of neural stem cells, neuronal hippocampal synaptic transmission, and brain phenotypes including shape and structures, in Pthrp knock-in mice, which express PTHrP (1-84), a truncated form of the protein that is missing the NLS and the C-terminal region of the protein, and their wild-type littermates. Results showed that Pthrp knock-in mice display abnormal brain shape and structures; decreased neural cell proliferative capacity and increased apoptosis associated with up-regulation of cyclin dependent kinase inhibitors p16, p21, p27 and p53 and down-regulation of the Bmi-1 oncogene; delayed neural cell differentiation; and impaired hippocampal synaptic transmission and plasticity. These findings provide in vivo experimental evidence that the NLS and C-terminus of PTHrP are essential not only for the regulation of neural cell proliferation and differentiation, but also for the maintenance of normal neuronal synaptic transmission and plasticity.
authors: State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Department of Anatomy, Histology and Embryology, Nanjing Medical University, Nanjing, Jiangsu, China.
authors: Zhen
authors: Z
authors: Gu
authors: Yahong
authors: Y
authors: Liu
authors: Yongjie
authors: Y
authors: Zhang
authors: Shulei
authors: S
authors: Jin
authors: Qi
authors: Q
authors: Chen
authors: David
authors: D
authors: Goltzman
authors: Andrew
authors: A
authors: Karaplis
authors: Dengshun
authors: D
authors: Miao
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000254:growth & development / Q000378:metabolism / Q000502:physiology*; D049109:Cell Proliferation; D055879:Gene Knock-In Techniques; D055786:Gene Knockout Techniques; D051379:Mice; D009473:Neuronal Plasticity; D009474:Neurons / Q000166:cytology; D019913:Nuclear Localization Signals; D044162:Parathyroid Hormone-Related Protein / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D009435:Synaptic Transmission
chemical_list: D019913:Nuclear Localization Signals; D044162:Parathyroid Hormone-Related Protein