p120 catenin is required for normal renal tubulogenesis and glomerulogenesis

Marciano, Denise K.; Brakeman, Paul; Lee, Chao Zong; Spivak, Natalie; Eastburn, Dennis J.; Bryant, David M.; Beaudoin, Gerard M.J.; Hofmann, Ilse; Mostov, Keith E.; Reichardt, Louis F.

doi:10.1242/dev.056564

Cited by 53 publications

(55 citation statements)

References 60 publications

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“…In fact, on average, p120-ablated tissues tend to retain 25-50% of cadherin levels found in control tissue Perez-Moreno et al, 2006;Smalley-Freed et al, 2010). In vivo correlations, where available, appear to support the in vitro data in that p120 family members have been found in tissues in which p120 ablation does not result in complete cadherin loss (Marciano et al, 2011;Perez-Moreno et al, 2006). However, whether endogenous p120 family members compensate for p120 loss in vivo has yet to be directly demonstrated in any tissue (e.g.…”

Section: Research Article P120-catenin In Mammary Developmentmentioning

confidence: 80%

“…Arvcf, p0071 (plakophilin 4) and d-catenin using wellcharacterized antibodies (Hofmann et al, 2009;Marciano et al, 2011;Walter et al, 2008;Walter et al, 2010). Family members demonstrated membranous and cytoplasmic localization in the mammary epithelium, which was not altered in the absence of p120 (Fig.…”

Section: Development 1758mentioning

confidence: 99%

“…Since immunostaining of E-cadherin and -catenin was dramatically decreased in the absence of p120, these data suggest that p120 family members, if present, are unable to compensate in this tissue. Therefore, we analyzed the expression of the p120 family members Arvcf, p0071 (plakophilin 4) and d-catenin using wellcharacterized antibodies (Hofmann et al, 2009;Marciano et al, 2011;Walter et al, 2008;Walter et al, 2010). Family members demonstrated membranous and cytoplasmic localization in the mammary epithelium, which was not altered in the absence of p120 (Fig.…”

Section: Research Article P120-catenin In Mammary Developmentmentioning

confidence: 99%

“…Phenotypes associated with p120 ablation in vivo appear to be largely tissue dependent and surprisingly unpredictable (Bartlett et al, 2010;Elia et al, 2006;Marciano et al, 2011;Oas et al, 2010;Perez-Moreno et al, 2006;SmalleyFreed et al, 2010;Stairs et al, 2011). For example, in the developing salivary gland, p120 ablation completely blocks acini formation .…”

Section: Introductionmentioning

confidence: 99%

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p120-catenin is essential for terminal end bud function and mammary morphogenesis

et al. 2012

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SUMMARYAlthough p120-catenin (p120) is crucial for E-cadherin function, ablation experiments in epithelial tissues from different organ systems reveal markedly different effects. Here, we examine for the first time the consequences of p120 knockout during mouse mammary gland development. An MMTV-Cre driver was used to target knockout to the epithelium at the onset of puberty. p120 ablation was detected in approximately one-quarter of the nascent epithelium at the forth week post-partum. However, p120 null cells were essentially nonadherent, excluded from the process of terminal end bud (TEB) morphogenesis and lost altogether by week six. This elimination process caused a delay in TEB outgrowth, after which the gland developed normally from cells that had retained p120. Mechanistic studies in vitro indicate that TEB dysfunction is likely to stem from striking E-cadherin loss, failure of cell-cell adhesion and near total exclusion from the collective migration process. Our findings reveal an essential role for p120 in mammary morphogenesis. RESEARCH ARTICLE p120-catenin in mammary developmentThe mammary gland provides an outstanding in vivo system for studying morphogenetic events (e.g. invasion and differentiation), as the majority of the development of this non-vital organ occurs after birth. Prior to puberty, the mammary gland exists as a rudimentary ductal tree. At the onset of puberty at ~3 weeks of age, proliferative structures at the tips of ducts, known as terminal end buds (TEBs), develop and begin to invade the surrounding stroma (Hinck and Silberstein, 2005). TEBs comprise a dynamic mass of E-cadherin-positive luminal body cells surrounded by a motile cap cell layer expressing P-cadherin (cadherin 3) (Daniel et al., 1995;Ewald et al., 2008; Hinck and Silberstein, 2005). The TEBs bifurcate repeatedly to form the ductal tree and, ultimately, the mature gland. This process, termed branching morphogenesis, concludes at ~10-12 weeks, when the TEBs have traversed the length of the fat pad and a fully developed ductal tree has formed (Cardiff and Wellings, 1999; Hennighausen and Robinson, 2005;Richert et al., 2000;. Disruption of TEBs is often associated with delayed ductal outgrowth and impaired branching morphogenesis, thus suggesting an essential function of TEBs in the overall development of the mammary gland (Jackson-Fisher et al., 2004;Kouros-Mehr et al., 2006;Lu et al., 2008;Parsa et al., 2008;Srinivasan et al., 2003;Sternlicht et al., 2006).Here, we examine the role of p120 in the developing mammary epithelium. MMTV promoter-driven Cre recombinase expression in p120 f/f mice was used to induce p120 ablation at the onset of puberty. In week 4, developing epithelial structures exhibited mosaic p120 ablation, the extent of which varied widely between mice. p120 loss in nascent ducts caused severe morphological defects (e.g. cell rounding and sloughing into the lumen), despite the presence of p120 family members, which were unable to compensate for p120 loss. p120 null cells were observed less frequently ...

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Section: Research Article P120-catenin In Mammary Developmentmentioning

confidence: 80%

Section: Development 1758mentioning

confidence: 99%

Section: Research Article P120-catenin In Mammary Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

p120-catenin is essential for terminal end bud function and mammary morphogenesis

et al. 2012

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“…Because membrane polarity proteins, e.g. E-cadherin, are known to be destabilized in the kidneys of PKD and NPHP patients (Charron et al, 2000;Marciano et al, 2011;Okada et al, 2000;Rocco et al, 1992;Wilson, 2011), and because we also observed a similar phenotype in pcy mice (supplementary material Fig. S4B), it is probable that both impairment of Slp2-a-mediated Rap-ezrin signaling and enhancement of cAMP-induced RapGEF signaling ultimately activate Rac1 and that the activated Rac1 causes cell spreading by destabilizing E-cadherin at the cell-cell junctions in the kidneys of pcy mice (supplementary material Fig.…”

Section: Discussionmentioning

confidence: 99%

Slp2-a controls renal epithelial cell size through regulation of Rap–ezrin signaling independently of Rab27

Yasuda

Fukuda

2013

Journal of Cell Science

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Synaptotagmin-like protein 2 (Slp2-a/Sytl2) is a Rab27 effector protein that regulates transport of Rab27-bearing vesicles and organelles through its N-terminal Rab27-binding domain and a phospholipid-binding C2A domain. Here we demonstrate a Rab27-independent function of Slp2-a in the control of renal cell size through a previously uncharacterized C2B domain. We found that by recruiting Rap1 GAPs to the plasma membrane of MDCK II cells through the C2B domain, Slp2-a inactivates Rap signaling and modulates the size of the cells. Functional ablation of Slp2-a resulted in an increase in the size of MDCK II cells. Drosophila Slp Bitesize was found to compensate for the function of Slp2-a in MDCK II cells, thereby indicating that the mechanism of the cell size control by Slp proteins has been evolutionarily conserved. Interestingly, blockade of the activity of ezrin, a downstream target of Rap, with the glucosylceramide synthase inhibitor, miglustat, effectively inhibited cell spreading of Slp2-a-knockdown cells. We also discovered aberrant expression of Slp2-a and increased activity of ezrin in pcy (Nphp3 pcy ) mice, a model of polycystic kidney disease that is characterized by renal cell spreading. Our findings indicate that Slp2-a controls renal cell size through regulation of Rap-ezrin signaling independently of Rab27.

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A combination of Wnt and growth factor signaling induces Arl4c expression to form epithelial tubular structures

et al. 2014

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Growth factor-dependent epithelial morphological changes and proliferation are essential for the formation of tubular structures, but the underlying molecular mechanisms are poorly understood. Co-stimulation with Wnt3a and epidermal growth factor (Wnt3a/ EGF) induced development of tubes consisting of intestinal epithelial cells by inducing expression of Arl4c, an Arf-like small GTPbinding protein, in three-dimensional culture, while stimulation with Wnt3a or EGF alone did not. Arl4c expression resulted in rearrangement of the cytoskeleton through activation of Rac and inactivation of Rho properly, which promoted cell growth by inducing nuclear translocation of Yes-associated protein and transcriptional co-activator with PDZ-binding motif (YAP/TAZ) in leading cells. Arl4c was expressed in ureteric bud tips and pretubular structures in the embryonic kidney. In an organoid culture assay, Wnt and fibroblast growth factor signaling simultaneously induced elongation and budding of kidney ureteric buds through Arl4c expression. YAP/TAZ was observed in the nucleus of extending ureteric bud tips. Thus, Arl4c expression induced by a combination of growth factor signaling mechanisms is involved in tube formation.

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p120 catenin is required for normal renal tubulogenesis and glomerulogenesis

Cited by 53 publications

References 60 publications

p120-catenin is essential for terminal end bud function and mammary morphogenesis

p120-catenin is essential for terminal end bud function and mammary morphogenesis

Slp2-a controls renal epithelial cell size through regulation of Rap–ezrin signaling independently of Rab27

A combination of Wnt and growth factor signaling induces Arl4c expression to form epithelial tubular structures

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