Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.
Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.
Kobayashi
Akio
A
Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138, USA.
Valerius
M Todd
MT
Mugford
Joshua W
JW
Carroll
Thomas J
TJ
Self
Michelle
M
Oliver
Guillermo
G
McMahon
Andrew P
AP
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002678:Chimera / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology* / Q000196:embryology / Q000502:physiology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009399:Nephrons / Q000166:cytology* / Q000196:embryology / Q000502:physiology; D038081:Organogenesis / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000235:genetics
D018398:Homeodomain Proteins; C497420:Six2 protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; C515303:Wnt9b protein, mouse