Talk:Renal System - Molecular

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Cite this page: Hill, M.A. (2021, November 30) Embryology Renal System - Molecular. Retrieved from


Epithelial cell fate in the nephron tubule is mediated by the ETS transcription factors etv5a and etv4 during zebrafish kidney development

Dev Biol. 2016 Mar 15;411(2):231-45. doi: 10.1016/j.ydbio.2016.01.035. Epub 2016 Jan 29.

Marra AN1, Wingert RA2.


Kidney development requires the differentiation and organization of discrete nephron epithelial lineages, yet the genetic and molecular pathways involved in these events remain poorly understood. The embryonic zebrafish kidney, or pronephros, provides a simple and useful model to study nephrogenesis. The pronephros is primarily comprised of two types of epithelial cells: transportive and multiciliated cells (MCCs). Transportive cells occupy distinct tubule segments and are characterized by the expression of various solute transporters, while MCCs function in fluid propulsion and are dispersed in a "salt-and-pepper" fashion within the tubule. Epithelial cell identity is reliant on interplay between the Notch signaling pathway and retinoic acid (RA) signaling, where RA promotes MCC fate by inhibiting Notch activity in renal progenitors, while Notch acts downstream to trigger transportive cell formation and block adoption of an MCC identity. Previous research has shown that the transcription factor ets variant 5a (etv5a), and its closely related ETS family members, are required for ciliogenesis in other zebrafish tissues. Here, we mapped etv5a expression to renal progenitors that occupy domains where MCCs later emerge. Thus, we hypothesized that etv5a is required for normal development of MCCs in the nephron. etv5a loss of function caused a decline of MCC number as indicated by the reduced frequency of cells that expressed the MCC-specific markers outer dense fiber of sperm tails 3b (odf3b) and centrin 4 (cetn4), where rescue experiments partially restored MCC incidence. Interestingly, deficiency of ets variant 4 (etv4), a related gene that is broadly expressed in the posterior mesoderm during somitogenesis stages, also led to reduced MCC numbers, which were further reduced by dual etv5a/4 deficiency, suggesting that both of these ETS factors are essential for MCC formation and that they also might have redundant activities. In epistatic studies, exogenous RA treatment expanded the etv5a domain within the renal progenitor field and RA inhibition blocked etv5a in this populace, indicating that etv5a acts downstream of RA. Additionally, treatment with exogenous RA partially rescued the reduced MCC phenotype after loss of etv5a. Further, abrogation of Notch with the small molecule inhibitor DAPT increased the renal progenitor etv5a expression domain as well as MCC density in etv5a deficient embryos, suggesting Notch acts upstream to inhibit etv5a. In contrast, etv4 levels in renal progenitors were unaffected by changes in RA or Notch signaling levels, suggesting a possible non-cell autonomous role during pronephros formation. Taken together, these findings have revealed new insights about the genetic mechanisms of epithelial cell development during nephrogenesis. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved. KEYWORDS: Epithelial cell fate; Kidney; Multiciliated cells; Nephrogenesis; Notch signaling; Pronephros; Retinoic acid; etv4; etv5a PMID 26827902

Growth Factors Receptors

Fgfr1, Fgfr2 Fibroblast Growth Factor Receptor 1, 2 early metanephric development UB, MM

Gfrα1 GDNF Family Receptor Alpha 1 outgrowth of cells from the WD towards the MM UB, MM

Notch 2 Neurogenic locus notch homolog protein 2 maturation of proximal end of the nephron MM

Ret Receptor tyrosine-protein kinase initial ureteric bud outgrowth from Wolfian duct, interacts with GDNF ureteric bud epithelial cells

Transcription Factors

BRN1 Brain-Specific Homeobox/POU Domain Protein 1 tubule formation S-shaped body

FoxC2 Forkhead Box C2 first signal in podocyte commtiment s-shaped body

LIM1 (LHX1) LIM homebox 1 initial stages of patterning in the renal vesicle PTA, c-shaped body

Osr1 Odd-Skipped Related Transcription Factor 1 giving rise to MM intermediate mesoderm, MM

Sall1 Spalt-Like Transcription Factor 1 ensures high level of GDNF production MM

Pax2 Paired box gene 2 Expression in the MM ensures high level of GDNF production UB epithelial cells and condensed MM

Wt1 Wilms tumor 1 ensures high level of GDNF production cap MM-high levels, stromal MM-low levels, glomerular progenitors

Other Signals

β-catenin cadherin-associated protein beta nephron formation in the early stage of kidney development several cell types

Eya1 Eyes absent homolog 1 very early kidney development MM

HoxA11, HoxC11, HoxD11 homeobox protein A11, C11, D11 early kidney development uninduced MM

Six1 Sine oculis-related homeobox 1 early kidney development uninduced MM

Six2 Sine oculis-related homeobox 2 maintain nephron progenitor cells subpopulation of cells in cap MM