Adam10 Mediates the Choice between Principal Cells and Intercalated Cells in the Kidney

Abstract

A disintegrin and metalloproteinase domain 10 (Adam10), a member of the ADAM family of cell membrane-anchored proteins, has been linked to the regulation of the Notch, EGF, E-cadherin, and other signaling pathways. However, it is unclear what role Adam10 has in the kidney in vivo. In this study, we showed that Adam10 deficiency in ureteric bud (UB) derivatives leads to a decrease in urinary concentrating ability, polyuria, and hydronephrosis in mice. Furthermore, Adam10 deficiency led to a reduction in the percentage of aquaporin 2 (Aqp2) + principal cells (PCs) in the collecting ducts that was accompanied by a proportional increase in the percentage of intercalated cells (ICs). This increase was more prominent in type A ICs than in type B ICs. Foxi1, a transcription factor important for the differentiation of ICs, was upregulated in the Adam10 mutants. The observed reduction of Notch activity in Adam10 mutant collecting duct epithelium and the similar reduction of PC/IC ratios in the collecting ducts in mice deficient for mindbomb E3 ubiquitin protein ligase 1, a key regulator of the Notch and Wnt/receptor-like tyrosine kinase signaling pathways, suggest that Adam10 regulates cell fate determination through the activation of Notch signaling, probably through the regulation of Foxi1 expression. However, phenotypic differences between the Adam10 mutants, the Mib1 mutants, and the Foxi1 mutants suggest that the functions of Adam10 in determining the fate of collecting duct cells are more complex than those of a simple upstream factor in a linear pathway involving Notch and Foxi1.

Elf5 is a principal cell lineage specific transcription factor in the kidney that contributes to Aqp 2 and Avpr 2 gene expression

“…Our observations extend previous studies of Mib1 and Adam10 deficient mice [23, 24] by uncovering a role for RBPJ and Presenilin1 and Presenilin2 in development of an appropriate number of principal cells within the collecting ducts. Together with the previous studies we confirm a role for the canonical Notch signaling pathway in ensuring the development of sufficient number of principal cells.…”

“…Foxi1 expression levels and the number of ICs are increased in Mind bomb1 (Mib1) and Adam10-deficient mouse collecting ducts. Both Mib1 and Adam10 are required for Notch receptor activation within the developing CD to ensure that a sufficient number of CD cells select the PC-fate [23, 24]. Collectively, the studies in different organisms reveal a central role for Foxi1 in specification of IC-like cells and a role for Notch signaling in repressing Foxi1 expression to allow for PC development.…”

Adaptation by the collecting duct to an exogenous acid load is blunted by deletion of the proton-sensing receptor GPR4

“…A growing number of reports have documented changes in the distribution of the subtypes of ICs in mice, rats, and rabbits during acid loading (72,82,103), lithium intoxication (21,92), acetazolamide administration (6), with kidney-specific hensin deletion (38), inactivation of notch signaling (46), or foxo1 transcription factor deficiency (11). Some of these changes are developmental, whereas others occur under certain conditions in adult animals.…”

ADAM10–Notch signaling governs the recruitment of ovarian pregranulosa cells and controls folliculogenesis in mice

“…ADAM10 is crucial for the regulation of various physiological processes such as cell proliferation, differentiation and death (Gibb et al, 2011;Glomski et al, 2011;Guo et al, 2015;Jorissen et al, 2010;Tsai et al, 2014;Weber et al, 2011;Zhang et al, 2010). It is well known that the regulatory roles of ADAM10 are closely related to Notch signaling (Weber and Saftig, 2012).…”