A role of the (pro)renin receptor in neuronal cell differentiation.
The (pro)renin receptor [(P)RR] plays a pivotal role in the renin-angiotensin system. Experimental models emphasize the role of (P)RR in organ damage associated with hypertension and diabetes. However, a mutation of the (P)RR gene, resulting in frame deletion of exon 4 [Delta4-(P)RR] is associated with X-linked mental retardation (XLMR) and epilepsy pointing to a novel role of (P)RR in brain development and cognitive function. We have studied (P)RR expression in mouse brain, as well as the effect of transfection of Delta4-(P)RR on neuronal differentiation of rat neuroendocrine PC-12 cells induced by nerve growth factor (NGF). In situ hybridization showed a wide distribution of (P)RR, including in key regions involved in the regulation of blood pressure and body fluid homeostasis. In mouse neurons, the receptor is on the plasma membrane and in synaptic vesicles, and stimulation by renin provokes ERK1/2 phosphorylation. In PC-12 cells, (P)RR localized mainly in the Golgi and in endoplasmic reticulum and redistributed to neurite projections during NGF-induced differentiation. In contrast, Delta4-(P)RR remained cytosolic and inhibited NGF-induced neuronal differentiation and ERK1/2 activation. Cotransfection of PC-12 cells with (P)RR and Delta4-(P)RR cDNA resulted in altered localization of (P)RR and inhibited (P)RR redistribution to neurite projections upon NGF stimulation. Furthermore, (P)RR dimerized with itself and with Delta4-(P)RR, suggesting that the XLMR and epilepsy phenotype resulted from a dominant-negative effect of Delta4-(P)RR, which coexists with normal transcript in affected males. In conclusion, our results show that (P)RR is expressed in mouse brain and suggest that the XLMR and epilepsy phenotype might result from a dominant-negative effect of the Delta4-(P)RR protein.
Contrepas
Aurelie
A
Institut National de la Santé et de la Recherche Médicale, Unit 833 and Collège de France, Experimental Medicine Unit, Paris, France.
Walker
Joy
J
Koulakoff
Annette
A
Franek
Karl J
KJ
Qadri
Fatimunnisa
F
Giaume
Christian
C
Corvol
Pierre
P
Schwartz
Charles E
CE
Nguyen
Genevieve
G
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004827:Epilepsy / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D038901:X-Linked Intellectual Disability / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015388:Organelles / Q000378:metabolism; D016716:PC12 Cells; D055503:Protein Multimerization / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D017966:Pyramidal Cells / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000502:physiology*; D012083:Renin / Q000494:pharmacology; D013572:Synaptic Vesicles / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D014162:Transfection; D000093342:Prorenin Receptor
D011956:Receptors, Cell Surface; D016708:Synaptophysin; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D012083:Renin; D000093342:Prorenin Receptor