title: Coffin-Lowry syndrome: a role for RSK2 in mammalian neurogenesis.
abstract: Coffin-Lowry Syndrome (CLS) is an X-linked genetic disorder associated with cognitive and behavioural impairments. CLS patients present with loss-of-function mutations in the RPS6KA3 gene encoding the mitogen-activated protein kinase (MAPK)-activated kinase p90 ribosomal S6 kinase 2 (Rsk2). Although Rsk2 is expressed in the embryonic brain, its function remains largely uncharacterized. To this end, we isolated murine cortical precursors at embryonic day 12 (E12), a timepoint when neuronal differentiation is initiated, and knocked-down Rsk2 expression levels using shRNA. We performed similar experiments in vivo using in utero electroporations to express shRNA against Rsk2. Rsk2 knockdown resulted in a significant decrease in neurogenesis and an increase in the proportion of proliferating Pax6-positive radial precursor cells, indicating that Rsk2 is essential for cortical radial precursors to differentiate into neurons. In contrast, reducing Rsk2 levels in vitro or in vivo had no effect on the generation of astrocytes. Thus, Rsk2 loss-of-function, as seen in CLS, perturbs the differentiation of neural precursors into neurons, and maintains them instead as proliferating radial precursor cells, a defect that may underlie the cognitive dysfunction seen in CLS.
authors.affiliation: Developmental and Stem Cell Biology Program, Hospital for Sick Children, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Chandrasagar B
authors.initials: CB
authors.lastname: Dugani
authors.forename: Annie
authors.initials: A
authors.lastname: Paquin
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
mesh_terms: D000818:Animals; D001483:Base Sequence; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D038921:Coffin-Lowry Syndrome / Q000196:embryology / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000235:genetics; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D034741:RNA, Small Interfering; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3