The role of small GTPases in neuronal morphogenesis and polarity

González-Billault, Christian; Muñoz-Llancao, Pablo; Henríquez, Daniel R.; Wojnacki, José; Conde, Cecı́lia; Cáceres, Alfredo

doi:10.1002/cm.21034

Cited by 102 publications

(99 citation statements)

References 285 publications

(374 reference statements)

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“…Digested adenoma fragments were then collected and cultured in between these factors. Disruption of the pathway by removing p120 leads to constitutive activation of RhoA and various actomyosin contractile phenotypes that include tension-dependent apoptosis (27,52,60,61). In MDCK cells, Src-and Rac1-mediated (but not Hras mediated) cell transformation is dependent on this pathway and blocked upon removal of p120 (52), and the inverted polarity phenotype described originally by Mostov and colleagues is similarly controlled (52,62).…”

Section: Methodsmentioning

confidence: 90%

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia

Short¹,

Kondo²,

Smalley-Freed³

et al. 2017

Journal of Clinical Investigation

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IntroductionThe vast majority of human colorectal cancer (CRC) is triggered by inactivation of the tumor suppressor adenomatous polyposis coli (APC) in one of several intestinal stem cells (ISCs) present in each intestinal crypt. The result is unscheduled translocation of β-catenin to the nucleus where tumorigenesis is initiated via interaction with the transcription factor TCF4 and unregulated transactivation of Wnt pathway target genes (e.g., AXIN2, MYC) (1-4). The ISC contributes several stem cell-restricted properties (e.g., self-renewal, mesenchymal characteristics) that are hijacked by the constitutively activated Wnt pathway and are essential for tumor initiation. Progression to malignancy involves subsequent genetic and epigenetic alterations, including mutations in genes such as KRAS, SMAD4, and TP53, which are frequently targeted in CRC, and a much larger number of less frequently mutated genes uncovered recently by whole genome sequencing. The transition to malignancy is often accompanied by the onset of metastasis, a phenomenon responsible for most cancer-related mortality and frequently linked to genetic and/or epigenetic dysregulation of the cell-cell adhesion receptor epithelial cadherin (E-cadherin) (5-8).E-cadherin is widely regarded as the principle organizer of the epithelial phenotype (9, 10). It functions as a classic tumor suppressor in diffuse gastric cancer (11) and lobular carcinoma of the breast (12), where germline mutations in the E-cadherin gene (CDH1) are responsible for familial inheritance of one mutant allele. Early loss of the second allele (i.e., loss of heterozygosity [LOH]) then plays a causal role in tumorigenesis (11)(12)(13). In the vast majority of epithelial cancers, however, E-cadherin is considered a metastasis suppressor because it is downregulated in advanced tumors and plays a causal role in the transition to metastasis (5,7,(14)(15)(16). Although factors underpinning the distinct differences in timing of E-cadherin loss between these groups are not understood, the former is frequently irreversible (e.g., gene mutation) while the latter often occurs by epithelial-to-mesenchymal transition (EMT) and is later reversed during colonization of distant sites (17).As with all classical cadherins, E-cadherin mediates specific adhesion of adjacent cells via homophilic interaction between extracellular domains (9). Strong E-cadherin-mediated adhesion, however, is absolutely dependent upon formation of a multimeric complex with 3 cytoplasmic binding partners, namely α-, β-, and p120-catenins (p120) (9,18). All members of the classical cadherin family, in fact, use these same core components to organize the actin cytoskeleton and coordinate signaling (9, 19). p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an "obligatory" haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated wi...

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Section: Methodsmentioning

confidence: 90%

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia

Short¹,

Kondo²,

Smalley-Freed³

et al. 2017

Journal of Clinical Investigation

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“…Cdc42 and Rac1 activities have been shown to be similarly regulated by sequential activation pathways from Cdc42 to Rac1 (Gonzalez-Billault et al, 2012). In contrast, AUTS2 uniquely regulates Rac1 and Cdc42 activities in opposing directions in neuronal cells.…”

Section: Discussionmentioning

confidence: 95%

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

Hori¹,

Nagai²,

Shan³

et al. 2014

Cell Reports

118

199

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Mutations in the Autism susceptibility candidate 2 gene (AUTS2), whose protein is believed to act in neuronal cell nuclei, have been associated with multiple psychiatric illnesses, including autism spectrum disorders, intellectual disability, and schizophrenia. Here we show that cytoplasmic AUTS2 is involved in the regulation of the cytoskeleton and neural development. Immunohistochemistry and fractionation studies show that AUTS2 localizes not only in nuclei, but also in the cytoplasm, including in the growth cones in the developing brain. AUTS2 activates Rac1 to induce lamellipodia but downregulates Cdc42 to suppress filopodia. Our loss-of-function and rescue experiments show that a cytoplasmic AUTS2-Rac1 pathway is involved in cortical neuronal migration and neuritogenesis in the developing brain. These findings suggest that cytoplasmic AUTS2 acts as a regulator of Rho family GTPases to contribute to brain development and give insight into the pathology of human psychiatric disorders with AUTS2 mutations.

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“…Therefore, the activity of RhoA is important for the establishment of neuronal polarity. Interestingly, RhoA activity is higher in the growth cones of minor neurites of polarized neurons than in the growing axon (Gonzalez-Billault et al, 2012). Rho kinase phosphorylates and inactivates p190 RhoGAP, a member of GTPase-activating proteins (GAPs; negative regulators of Rho family proteins), leading to sustained RhoA activation (Mori et al, 2009).…”

Section: Rho Family Proteins In Neuronal Polaritymentioning

confidence: 99%

Neuronal polarization

et al. 2015

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Neurons are highly polarized cells with structurally and functionally distinct processes called axons and dendrites. This polarization underlies the directional flow of information in the central nervous system, so the establishment and maintenance of neuronal polarization is crucial for correct development and function. Great progress in our understanding of how neurons establish their polarity has been made through the use of cultured hippocampal neurons, while recent technological advances have enabled in vivo analysis of axon specification and elongation. This short review and accompanying poster highlight recent advances in this fascinating field, with an emphasis on the signaling mechanisms underlying axon and dendrite specification in vitro and in vivo.

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The role of small GTPases in neuronal morphogenesis and polarity

Cited by 102 publications

References 285 publications

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia

Cytoskeletal Regulation by AUTS2 in Neuronal Migration and Neuritogenesis

Neuronal polarization

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