The cdx genes and retinoic acid control the positioning and segmentation of the zebrafish pronephros.
Kidney function depends on the nephron, which comprises a blood filter, a tubule that is subdivided into functionally distinct segments, and a collecting duct. How these regions arise during development is poorly understood. The zebrafish pronephros consists of two linear nephrons that develop from the intermediate mesoderm along the length of the trunk. Here we show that, contrary to current dogma, these nephrons possess multiple proximal and distal tubule domains that resemble the organization of the mammalian nephron. We examined whether pronephric segmentation is mediated by retinoic acid (RA) and the caudal (cdx) transcription factors, which are known regulators of segmental identity during development. Inhibition of RA signaling resulted in a loss of the proximal segments and an expansion of the distal segments, while exogenous RA treatment induced proximal segment fates at the expense of distal fates. Loss of cdx function caused abrogation of distal segments, a posterior shift in the position of the pronephros, and alterations in the expression boundaries of raldh2 and cyp26a1, which encode enzymes that synthesize and degrade RA, respectively. These results suggest that the cdx genes act to localize the activity of RA along the axis, thereby determining where the pronephros forms. Consistent with this, the pronephric-positioning defect and the loss of distal tubule fate were rescued in embryos doubly-deficient for cdx and RA. These findings reveal a novel link between the RA and cdx pathways and provide a model for how pronephric nephrons are segmented and positioned along the embryonic axis.
Wingert
Rebecca A
RA
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
Selleck
Rori
R
Yu
Jing
J
Song
Huai-Dong
HD
Chen
Zhu
Z
Song
Anhua
A
Zhou
Yi
Y
Thisse
Bernard
B
Thisse
Christine
C
McMahon
Andrew P
AP
Davidson
Alan J
AJ
D000818:Animals; D003001:Cloning, Molecular; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D017403:In Situ Hybridization; D007668:Kidney / Q000196:embryology*; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*; D015027:Zebrafish
D018398:Homeodomain Proteins; D014157:Transcription Factors; D014212:Tretinoin