title: Inversin modulates the cortical actin network during mitosis.
abstract: Mutations in inversin cause nephronophthisis type II, an autosomal recessive form of polycystic kidney disease associated with situs inversus, dilatation, and kidney cyst formation. Since cyst formation may represent a planar polarity defect, we investigated whether inversin plays a role in cell division. In developing nephrons from inv-/- mouse embryos we observed heterogeneity of nuclear size, increased cell membrane perimeters, cells with double cilia, and increased frequency of binuclear cells. Depletion of inversin by siRNA in cultured mammalian cells leads to an increase in bi- or multinucleated cells. While spindle assembly, contractile ring formation, or furrow ingression appears normal in the absence of inversin, mitotic cell rounding and the underlying rearrangement of the cortical actin cytoskeleton are perturbed. We find that inversin loss causes extensive filopodia formation in both interphase and mitotic cells. These cells also fail to round up in metaphase. The resultant spindle positioning defects lead to asymmetric division plane formation and cell division. In a cell motility assay, fibroblasts isolated from inv-/- mouse embryos migrate at half the speed of wild-type fibroblasts. Together these data suggest that inversin is a regulator of cortical actin required for cell rounding and spindle positioning during mitosis. Furthermore, cell division defects resulting from improper spindle position and perturbed actin organization contribute to altered nephron morphogenesis in the absence of inversin.
authors.affiliation: Department of Anatomy and Cell Biology, Indiana University, Indianapolis, IN, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Werner
authors.forename: Heather H
authors.initials: HH
authors.lastname: Ward
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Phillips
authors.forename: Caroline
authors.initials: C
authors.lastname: Miller
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Gattone
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bacallao
mesh_terms: D000199:Actins / Q000502:physiology*; D000818:Animals; D054443:Cell Migration Assays; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007672:Kidney Cortex / Q000166:cytology* / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008938:Mitosis / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; C491947:Invs protein, mouse; D014157:Transcription Factors
keywords: actin; cytoskeleton; mitosis; mitotic spindle; polycystic kidney disease