Sall1 Maintains Nephron Progenitors and Nascent Nephrons by Acting as Both an Activator and a Repressor

Kanda, Shoichiro; Tanigawa, Shunsuke; Ohmori, Tomoko; Taguchi, Atsuhiro; Kudo, Kuniko; Suzuki, Yutaka; Sato, Yuki; Hino, Shinjiro; Sander, Maike; Perantoni, Alan O.; Sugano, Sumio; Nakao, Mitsuyoshi; Nishinakamura, Ryuichi

doi:10.1681/asn.2013080896

Cited by 70 publications

(82 citation statements)

References 35 publications

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“…At 11.5 dpc, ROBO2 was detected in the SIX2 þ MM population of cells surrounding the UB, supporting previous findings that Robo2 is a direct target gene of SIX2 ( Fig. 1C) (Kanda et al, 2014).…”

Section: Robo2 Is Expressed In the Nephrogenic Cord And Six2 þ Metanesupporting

confidence: 89%

ROBO2 restricts the nephrogenic field and regulates Wolffian duct–nephrogenic cord separation

Wainwright

Wilhelm

Combes

et al. 2015

Developmental Biology

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ROBO2 plays a key role in regulating ureteric bud (UB) formation in the embryo, with mutations in humans and mice leading to supernumerary kidneys. Previous studies have established that the number and position of UB outgrowths is determined by the domain of metanephric mesenchymal Gdnf expression, which is expanded anteriorly in Robo2 mouse mutants. To clarify how this phenotype arises, we used high-resolution 3D imaging to reveal an increase in the number of nephrogenic cord cells, leading to extension of the metanephric mesenchyme field in Robo2-null mouse embryos. Ex vivo experiments suggested a dependence of this effect on proliferative signals from the Wolffian duct. Loss of Robo2 resulted in a failure of the normal separation of the mesenchyme from the Wolffian duct/ureteric epithelium, suggesting that aberrant juxtaposition of these two compartments in Robo2-null mice exposes the mesenchyme to abnormally high levels of proliferative stimuli. Our data suggest a new model in which SLIT-ROBO signalling acts not by attenuating Gdnf expression or activity, but instead by limiting epithelial/mesenchymal interactions in the nascent metanephros and restricting the extent of the nephrogenic field. These insights illuminate the aetiology of multiplex kidney formation in human individuals with ROBO2 mutations.

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Section: Robo2 Is Expressed In the Nephrogenic Cord And Six2 þ Metanesupporting

confidence: 89%

ROBO2 restricts the nephrogenic field and regulates Wolffian duct–nephrogenic cord separation

Wainwright

Wilhelm

Combes

et al. 2015

Developmental Biology

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“…Reductions of integrina8 and N-cadherin in both mutants suggest that adhesion to the ureteric bud niche and cell-to-cell adhesion between the progenitors (i.e., mesenchymal condensation) are required for the progenitor maintenance. However, progenitor depletion at E14.5 was not as severe as that observed in Sall1-deficient mice, which we reported recently, 30 and Kif26 mutants showed no kidney size reduction and survived to adulthood. It is likely that the progenitor pool is larger than that required and that its mild reduction alone, without any defects in nascent nephrons, does not result in a severe loss of nephrons.…”

Section: Discussionsupporting

confidence: 51%

Nonmuscle Myosin II Regulates the Morphogenesis of Metanephric Mesenchyme–Derived Immature Nephrons

Recuenco¹,

Ohmori²,

Tanigawa³

et al. 2015

Journal of the American Society of Nephrology

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The kidney develops from reciprocal interactions between the metanephric mesenchyme and ureteric bud. The mesenchyme transforms into epithelia and forms complicated nephron structures, whereas the ureteric bud extends its pre-existing epithelial ducts. Although the roles are well established for extracellular stimuli, such as Wnt and Notch, it is unclear how the intracellular cytoskeleton regulates these morphogenetic processes. Myh9 and Myh10 encode nonmuscle myosin II heavy chains, and Myh9 mutations in humans are implicated in congenital kidney diseases and focal segmental glomerulosclerosis in adults. Here, we analyzed the roles of Myh9 and Myh10 in the developing kidney. Ureteric bud-specific depletion of Myh9 resulted in no apparent phenotypes, whereas mesenchyme-specific Myh9 deletion caused proximal tubule dilations and renal failure. Mesenchyme-specific Myh9/Myh10 mutant mice died shortly after birth and showed a severe defect in nephron formation. The nascent mutant nephrons failed to form a continuous lumen, which likely resulted from impaired apical constriction of the elongating tubules. In addition, nephron progenitors lacking Myh9/Myh10 or the possible interactor Kif26b were less condensed at midgestation and reduced at birth. Taken together, nonmuscle myosin II regulates the morphogenesis of immature nephrons derived from the metanephric mesenchyme and the maintenance of nephron progenitors. Our data also suggest that Myh9 deletion in mice results in failure to maintain renal tubules but not in glomerulosclerosis.

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“…Human kidney development initiates at 5 weeks with the invasion of the ureteric bud and terminates around 36 weeks. Consequently, the 16 week human kidney is approximately one-third of the way through the active period of nephrogenesis, analogous to the E15.5-E16.5 mouse kidney, a developmental stage extensively characterized for Six2 regulation in earlier studies (Park et al, 2012;Kanda et al, 2014). Additionally, the kidney appears to be undergoing active branching until at least 20 weeks of gestation (L.L.O.…”

Section: Resultsmentioning

confidence: 99%

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

et al. 2016

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Nephron endowment is determined by the self-renewal and induction of a nephron progenitor pool established at the onset of kidney development. In the mouse, the related transcriptional regulators Six1 and Six2 play non-overlapping roles in nephron progenitors. Transient Six1 activity prefigures, and is essential for, active nephrogenesis. By contrast, Six2 maintains later progenitor selfrenewal from the onset of nephrogenesis. We compared the regulatory actions of Six2 in mouse and human nephron progenitors by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq). Surprisingly, SIX1 was identified as a SIX2 target unique to the human nephron progenitors. Furthermore, RNAseq and immunostaining revealed overlapping SIX1 and SIX2 activity in 16 week human fetal nephron progenitors. Comparative bioinformatic analysis of human SIX1 and SIX2 ChIP-seq showed each factor targeted a similar set of cis-regulatory modules binding an identical target recognition motif. In contrast to the mouse where Six2 binds its own enhancers but does not interact with DNA around Six1, both human SIX1 and SIX2 bind homologous SIX2 enhancers and putative enhancers positioned around SIX1. Transgenic analysis of a putative human SIX1 enhancer in the mouse revealed a transient, mouse-like, pre-nephrogenic, Six1 regulatory pattern. Together, these data demonstrate a divergence in SIX-factor regulation between mouse and human nephron progenitors. In the human, an auto/cross-regulatory loop drives continued SIX1 and SIX2 expression during active nephrogenesis. By contrast, the mouse establishes only an auto-regulatory Six2 loop. These data suggest differential SIX-factor regulation might have contributed to species differences in nephron progenitor programs such as the duration of nephrogenesis and the final nephron count.

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Sall1 Maintains Nephron Progenitors and Nascent Nephrons by Acting as Both an Activator and a Repressor

Cited by 70 publications

References 35 publications

ROBO2 restricts the nephrogenic field and regulates Wolffian duct–nephrogenic cord separation

ROBO2 restricts the nephrogenic field and regulates Wolffian duct–nephrogenic cord separation

Nonmuscle Myosin II Regulates the Morphogenesis of Metanephric Mesenchyme–Derived Immature Nephrons

Differential regulation of mouse and human nephron progenitors by the Six family of transcriptional regulators

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