The Rho GTPase Cdc42 is required for primary mammary epithelial cell morphogenesis in vitro

Bray, Kristi; Brakebusch, Cord; Vargo-Gogola, Tracy

doi:10.4161/sgtp.2.5.18163

Cited by 25 publications

(35 citation statements)

References 47 publications

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“…Indeed, the deletion of Cdc42 in pre-pregnant mammary epithelial cells has been reported to disrupt intact epithelial structures during acinar formation, due to defects in apical-basal cell polarity, cell-cell adherens structures, and tight junctions (17,18). While Cdc42 has also been suggested to be important for establishing basement membrane structures by controlling stromal-epithelial interactions, as well as for the deposition and processing of extracellular matrix proteins in pre-pregnant mammary glands (16,25), we did not detect any disruption of basement membrane structures, nor histological differences in stromal layers, in lactating CCKO mammary alveoli.…”

Section: Discussionmentioning

confidence: 99%

“…Because the deletion or loss of Cdc42 function has been shown to cause impairments in cell proliferation and increased apoptosis in pre-pregnant mammary ductal epithelial cells (17,18), we examined whether the deletion of Cdc42 in mammary luminal alveolar cells resulted in similar defects, thereby leading to latent alveologenesis. Prolactin-dependent signaling is critical for the proper morphogenesis and secretory capability of mammary gland cells during pregnancy and lactation (15).…”

Section: Cdc42 Knock-out Mothers Are Unable To Sufficiently Nourishmentioning

confidence: 99%

“…A modest increase in Cdc42 expression (1.5-fold) was sufficient for pre-pregnant mammary ductal epithelial cells to exhibit more invasive phenotypes, thus suggesting that the tight regulation of Cdc42 function is essential for this stage of mammary gland development (16). Studies in three-dimensional cell culture model systems, using pre-pregnant stage primary mammary epithelial cells, showed that the deletion of Cdc42 inhibited acinar formation by causing defects in apical-basal cell polarity, cell-cell contact, mitotic spindle orientation, cell proliferation, and cell survival (17). Additionally, the expression of the dominant negative Cdc42(T17N) mutant also inhibited the establishment of acinar structures and, consequently, prolactin-dependent synthesis of milk proteins in mammary epithelial cells (18).…”

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confidence: 99%

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An Essential Role for Cdc42 in the Functioning of the Adult Mammary Gland

Druso¹,

Endo²,

Lin³

et al. 2016

Journal of Biological Chemistry

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The Rho family small GTPase Cdc42 has been implicated in a wide range of cellular functions including the establishment of cell polarity and the remodeling of the actin cytoskeletal architecture, resulting in the tight regulation of cell growth and survival during developmental processes. The complete knock-out of Cdc42 in the mouse is embryonic-lethal, and its targeted deletion in various tissues has been shown to disrupt tissue homeostasis. Thus far, in most studies, the targeted deletion of Cdc42 occurred during embryogenesis. Here, we have used a conditional gene deletion strategy in mice to probe the specific role of Cdc42 during adult mammary gland function. Cdc42 conditional-knock-out females were unable to adequately nourish their pups, due to a disorganized epithelial compartment within their mammary glands. A closer examination showed that their mammary epithelial cells were not able to maintain functional alveolar lumens, due to an inability to establish normal apical/basal epithelial polarity, as well as proper cell-cell contacts. Loss of these essential epithelial characteristics led to a premature sloughing off of the Cdc42-null epithelial cells. Overall our findings demonstrate that Cdc42 plays essential roles in mammary gland function post pregnancy, where it helps to establish proper epithelial cell polarity and tissue homeostasis during lactation.

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Section: Discussionmentioning

confidence: 99%

Section: Cdc42 Knock-out Mothers Are Unable To Sufficiently Nourishmentioning

confidence: 99%

mentioning

confidence: 99%

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An Essential Role for Cdc42 in the Functioning of the Adult Mammary Gland

Druso¹,

Endo²,

Lin³

et al. 2016

Journal of Biological Chemistry

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“…Over a decade ago, studies showed that it was essential for in vitro EC lumen formation (Bayless and Davis, 2002;Davis et al, 2011). Cdc42 was then shown to be similarly required for lumen formation in epithelial systems, both in vitro (Bray et al, 2011;Bryant et al, 2010;Martin-Belmonte and Mostov, 2007) and in vivo (Kesavan et al, 2009;Melendez et al, 2011). Many functions have since been ascribed to Cdc42, from regulation of exocytosis and apical membrane biogenesis during tubulogenesis (Bryant et al, 2010) to ADAM17-mediated VEGFR2 (Kdr -Mouse Genome Informatics) shedding (Jin et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Many functions have since been ascribed to Cdc42, from regulation of exocytosis and apical membrane biogenesis during tubulogenesis (Bryant et al, 2010) to ADAM17-mediated VEGFR2 (Kdr -Mouse Genome Informatics) shedding (Jin et al, 2013). During mammalian tissue development, Cdc42 is ubiquitously expressed at the transcriptional level (see genepaint.org for a digital atlas of gene expression patterns in the mouse) and has been shown to be required for the development of many tissues, including the embryonic vasculature (Bray et al, 2011;Garvalov et al, 2007;Jin et al, 2013;Reginensi et al, 2013;Yang et al, 2007a). However, it remains unclear which cellular events Cdc42 controls and how it supports blood vessel morphogenesis.…”

Section: Introductionmentioning

confidence: 99%

Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation

Barry

Meadows

et al. 2015

Development

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The Rho family of small GTPases has been shown to be required in endothelial cells (ECs) during blood vessel formation. However, the underlying cellular events controlled by different GTPases remain unclear. Here, we assess the cellular mechanisms by which Cdc42 regulates mammalian vascular morphogenesis and maintenance. In vivo deletion of Cdc42 in embryonic ECs (Cdc42 Tie2KO ) results in blocked lumen formation and endothelial tearing, leading to lethality of mutant embryos by E9-10 due to failed blood circulation. Similarly, inducible deletion of Cdc42 (Cdc42 Cad5KO ) at mid-gestation blocks angiogenic tubulogenesis. By contrast, deletion of Cdc42 in postnatal retinal vessels leads to aberrant vascular remodeling and sprouting, as well as markedly reduced filopodia formation. We find that Cdc42 is essential for organization of EC adhesion, as its loss results in disorganized cell-cell junctions and reduced focal adhesions. Endothelial polarity is also rapidly lost upon Cdc42 deletion, as seen by failed localization of apical podocalyxin (PODXL) and basal actin. We link observed failures to a defect in F-actin organization, both in vitro and in vivo, which secondarily impairs EC adhesion and polarity. We also identify Cdc42 effectors Pak2/4 and N-WASP, as well as the actomyosin machinery, to be crucial for EC actin organization. This work supports the notion of Cdc42 as a central regulator of the cellular machinery in ECs that drives blood vessel formation.

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CDC42 Gtpase Activation Affects Hela Cell DNA Repair and Proliferation Following UV Radiation‐Induced Genotoxic Stress

Ascer

Magalhães

Espinha

et al. 2015

J of Cellular Biochemistry

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Cell division control protein 42 (CDC42) homolog is a small Rho GTPase enzyme that participates in such processes as cell cycle progression, migration, polarity, adhesion, and transcription. Recent studies suggest that CDC42 is a potent tumor suppressor in different tissues and is related to aging processes. Although DNA damage is crucial in aging, a potential role for CDC42 in genotoxic stress remains to be explored. Migration, survival/proliferation and DNA damage/repair experiments were performed to demonstrate CDC42 involvement in the recovery of HeLa cells exposed to ultraviolet radiation-induced stress. Sub-lines of HeLa cells ectopically expressing the constitutively active CDC42-V12 mutant were generated to examine whether different CDC42-GTP backgrounds might reflect different sensitivities to UV radiation. Our results show that CDC42 constitutive activation does not interfere with HeLa cell migration after UV radiation. However, the minor DNA damage exhibited by the CDC42-V12 mutant exposed to UV radiation most likely results in cell cycle arrest at the G2/M checkpoint and reduced proliferation and survival. HeLa cells and Mock clones, which express endogenous wild-type CDC42 and show normal activity, are more resistant to UV radiation. None of these effects are altered by pharmacological CDC42 inhibition. Finally, the phosphorylation status of the DNA damage response proteins γ-H2AX and p-Chk1 was found to be delayed and attenuated, respectively, in CDC42-V12 clones. In conclusion, the sensitivity of HeLa cells to ultraviolet radiation increases with CDC42 over-activation due to inadequate DNA repair signaling, culminating in G2/M cell accumulation, which is translated into reduced cellular proliferation and survival.

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The Rho GTPase Cdc42 is required for primary mammary epithelial cell morphogenesis in vitro

Cited by 25 publications

References 47 publications

An Essential Role for Cdc42 in the Functioning of the Adult Mammary Gland

An Essential Role for Cdc42 in the Functioning of the Adult Mammary Gland

Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation

CDC42 Gtpase Activation Affects Hela Cell DNA Repair and Proliferation Following UV Radiation‐Induced Genotoxic Stress

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