title: PCP4 (PEP19) overexpression induces premature neuronal differentiation associated with Ca(2+) /calmodulin-dependent kinase II-δ activation in mouse models of Down syndrome.
abstract: Pcp4/pep19 is a modulator of Ca(2+) -CaM, a key molecule for calcium signaling, expressed in postmitotic neuroectoderm cells during mouse embryogenesis. The PCP4 gene is located on human chromosome 21 and is present in three copies in Down syndrome (DS). To evaluate the consequences of three copies of this gene on the development of these cells in the nervous system, we constructed a transgenic (TgPCP4) mouse model, with one copy of human PCP4, and investigated the effects in this model and in the Ts1Cje, a mouse model of DS. During embryogenesis, we analyzed 1) the level of pcp4 transcript and protein in the two models; 2) the extent of colabeling for markers of neuronal differentiation (βIII-tubulin, Map2c, calbindin, and calretinin) and pcp4 by immunofluorescence analysis and overall protein levels of these markers by Western blotting; and 3) the rate of activation of CaMKII, a Ca(2+) -CaM target, to evaluate the impact of pcp4 overexpression on the Ca(2+) -CaM signaling pathway. We showed that three copies of the pcp4 gene induced the overexpression of transcripts and proteins during embryogenesis. Pcp4 overexpression 1) induced precocious neuronal differentiation, as shown by the distribution and levels of early neuronal markers; and 2) was associated with an increase in CaMKIIδ activation, confirming involvement in neuronal differentiation in vivo via a Pcp4-Ca(2+) -CaM pathway. TgPCP4 and Ts1Cje mice developed similar modifications, demonstrating that these mechanisms may account for abnormal neuronal development in DS.
authors.affiliation: Functional Adaptive Biology (BFA), Centre National de la Recherche Scientifique (CNRS) EAC4413, Université Paris Diderot-Paris7, 75205 Paris Cedex 13, France.
authors.forename: François
authors.initials: F
authors.lastname: Mouton-Liger
authors.forename: Sophie
authors.initials: S
authors.lastname: Thomas
authors.forename: Revital
authors.initials: R
authors.lastname: Rattenbach
authors.forename: Laetitia
authors.initials: L
authors.lastname: Magnol
authors.forename: Vanessa
authors.initials: V
authors.lastname: Larigaldie
authors.forename: Aurelie
authors.initials: A
authors.lastname: Ledru
authors.forename: Yann
authors.initials: Y
authors.lastname: Herault
authors.forename: Catherine
authors.initials: C
authors.lastname: Verney
authors.forename: Nicole
authors.initials: N
authors.lastname: Créau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D064032:Calbindin 2; D064026:Calbindins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D004314:Down Syndrome / Q000503:physiopathology*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015415:Biomarkers; C576764:CALB2 protein, human; C576511:Calb2 protein, mouse; D064032:Calbindin 2; D064026:Calbindins; D009419:Nerve Tissue Proteins; C489091:Pcp4 protein, mouse; D064030:S100 Calcium Binding Protein G; C050394:PCP4 protein, human; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2