title: Collective cell migration drives morphogenesis of the kidney nephron.
abstract: Tissue organization in epithelial organs is achieved during development by the combined processes of cell differentiation and morphogenetic cell movements. In the kidney, the nephron is the functional organ unit. Each nephron is an epithelial tubule that is subdivided into discrete segments with specific transport functions. Little is known about how nephron segments are defined or how segments acquire their distinctive morphology and cell shape. Using live, in vivo cell imaging of the forming zebrafish pronephric nephron, we found that the migration of fully differentiated epithelial cells accounts for both the final position of nephron segment boundaries and the characteristic convolution of the proximal tubule. Pronephric cells maintain adherens junctions and polarized apical brush border membranes while they migrate collectively. Individual tubule cells exhibit basal membrane protrusions in the direction of movement and appear to establish transient, phosphorylated Focal Adhesion Kinase-positive adhesions to the basement membrane. Cell migration continued in the presence of camptothecin, indicating that cell division does not drive migration. Lengthening of the nephron was, however, accompanied by an increase in tubule cell number, specifically in the most distal, ret1-positive nephron segment. The initiation of cell migration coincided with the onset of fluid flow in the pronephros. Complete blockade of pronephric fluid flow prevented cell migration and proximal nephron convolution. Selective blockade of proximal, filtration-driven fluid flow shifted the position of tubule convolution distally and revealed a role for cilia-driven fluid flow in persistent migration of distal nephron cells. We conclude that nephron morphogenesis is driven by fluid flow-dependent, collective epithelial cell migration within the confines of the tubule basement membrane. Our results establish intimate links between nephron function, fluid flow, and morphogenesis.
authors.affiliation: Nephrology Division, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Vasilyev
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Sudha
authors.initials: S
authors.lastname: Mudumana
authors.forename: Steve
authors.initials: S
authors.lastname: Mangos
authors.forename: Pui-Ying
authors.initials: PY
authors.lastname: Lam
authors.forename: Arindam
authors.initials: A
authors.lastname: Majumdar
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhao
authors.forename: Kar-Lai
authors.initials: KL
authors.lastname: Poon
authors.forename: Igor
authors.initials: I
authors.lastname: Kondrychyn
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korzh
authors.forename: Iain A
authors.initials: IA
authors.lastname: Drummond
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002465:Cell Movement; D017931:DNA Primers; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D009024:Morphogenesis; D009399:Nephrons / Q000166:cytology* / Q000196:embryology*; D015027:Zebrafish
chemical_list: D017931:DNA Primers