Transcriptional control of terminal nephron differentiation

Abstract

entiation of epithelial cells into more specialized cell types is a critical step in organogenesis. Throughout the process of terminal differentiation, epithelial progenitors acquire or upregulate expression of renal function genes and cease to proliferate, while expression of embryonic genes is repressed. This exquisite coordination of gene expression is accomplished by signaling networks and transcription factors which couple the external environment with the new functional demands of the cell. While there has been much progress in understanding the early steps involved in renal epithelial cell differentiation, a major gap remains in our knowledge of the factors that control the steps of terminal differentiation. A number of signaling molecules and transcription factors have been recently implicated in determining segmental nephron identity and functional differentiation. While some of these factors (the p53 gene family, hepatocyte nuclear factor-1␤) promote the terminal epithelial differentiation fate, others (Notch, Brn-1, IRX, KLF4, and Foxi1) tend to regulate differentiation of specific nephron segments and individual cell types. This review summarizes current knowledge related to these transcription factors and discusses how diverse cellular signals are integrated to generate a transcriptional output during the process of terminal differentiation. Since these transcriptional processes are accompanied by profound changes in nuclear chromatin structure involving the genes responsible for creating and maintaining the differentiated cell phenotype, future studies should focus on identifying the nature of these epigenetic events and factors, how they are regulated temporally and spatially, and the chromatin environment they eventually reside in. transcription factors; kidney development; p53; gene expression TERMINAL DIFFERENTIATION IS a key biological process characterized by cell cycle arrest and acquisition of specialized functions by each cell type. The genetic programs that couple cellular growth to functional differentiation are a subject of intense investigation (78). There is increasing appreciation that although formation of adequate numbers of nephrons (i.e., renal mass) is critical for achieving optimal renal function capacity, the signals that determine how, when, and which renal epithelial cells should acquire a given functional phenotype are equally essential. Aberrant terminal differentiation is a hallmark of dysplasia, cyst formation, and cancer, and therapeutic interventions to promote differentiation and cell cycle arrest [e.g., EGF receptor (EGFR) antagonists and histone deacetylase inhibitors] are effective measures in some models of polycystic kidney disease and cancer (17,26,72,73). Therefore, identification of factors that couple cell cycle arrest with functional differentiation is of great clinical importance. Termination of Nephrogenesis and Differentiation are Dynamic and Coordinated ProcessesThe metanephric kidney is derived from the intermediate mesoderm at embryonic (E) day 10.5 (E...

ZONAB Promotes Proliferation and Represses Differentiation of Proximal Tubule Epithelial Cells

“…32 Although no repressor of ZONAB is known, an attractive candidate is p53, which represses proliferation genes (PCNA, cdc2) while inducing cellcycle arrest genes (p21) and renal function genes. 33 Regulation by proteasomal degradation has been reported for multiple transcription factors such as the ZONAB-related, YB-1, and hypoxia-inducible factor but without direct link with epithelial polarization. Interestingly, von Hippel-Lindau factor (VHF), frequently defective in RCCs, is a ubiquitinligase of hypoxia-inducible factor, thereby normally acting as anti-oncogene regulating multiple targets.…”

FOXL2: a central transcription factor of the ovary

“…Other paralogs such as FOXA1, FOXA2, FOXI1, FOXP3 and FOXG1 are also required for the determination of specific cell lineages (Lee et al 2005b, El-Dahr et al 2008, Danesin & Houart 2012, Ohkura et al 2013. It has been proposed that FOXA1 and FOXA2 play the role of pioneer TFs, which are able to remodel chromatin in a lineage-specific way.…”

The Anion Exchanger Pendrin (SLC26A4) and Renal Acid-base Homeostasis

“…Several factors that affect intercalated cell differentiation in mouse kidney have been described including Foxi1, CP2L1, the bradykinin receptor 2, and putatively Klf4 [27][28][29][30].…”