Rap1 GTPases Are Master Regulators of Neural Cell Polarity in the Developing Neocortex

Shah, Bhavin; Lutter, Daniela; Tsytsyura, Yaroslav; Glyvuk, Natalia; Sakakibara, Akira; Klingauf, Jürgen; Püschel, Andreas W.

doi:10.1093/cercor/bhv341

Cited by 33 publications

(56 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rap1 proteins are members of the Ras subfamily of small GTPases involved in many biological responses, e.g. cell-cell (1) and cell-extracellular matrix attachment (2,3), cytoskeletal dynamics (4 -6), endocytosis/exocytosis (7)(8)(9)(10), polarity (11), cell proliferation (12)(13)(14)(15)(16), apoptosis (17)(18)(19), differentiation (20 -22), and migration/invasion (23). Like all small GTPases, they work as molecular allosteric units switching between inactive and active conformations in a regulated fashion with kinetic rate constants modulated by guanine-exchange factors and GTPase-activating proteins (24).…”

mentioning

confidence: 99%

Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase

Zhang

Cao

Barila

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Rap1 proteins are members of the Ras subfamily of small GTPases involved in many biological responses, including adhesion, cell proliferation, and differentiation. Like all small GTPases, they work as molecular allosteric units that are active in signaling only when associated with the proper membrane compartment. Prenylation, occurring in the cytosol, is an enzymatic posttranslational event that anchors small GTPases at the membrane, and prenyl-binding proteins are needed to mask the cytoplasm-exposed lipid during transit to the target membrane. However, several of these proteins still await discovery. In this study, we report that cyclase-associated protein 1 (CAP1) binds Rap1. We found that this binding is GTP-independent, does not involve Rap1's effector domain, and is fully contained in its C-terminal hypervariable region (HVR). Furthermore, Rap1 prenylation was required for high-affinity interactions with CAP1 in a geranylgeranyl-specific manner. The prenyl binding specifically involved CAP1's C-terminal hydrophobic β-sheet domain. We present a combination of experimental and computational approaches, yielding a model whereby the high-affinity binding between Rap1 and CAP1 involves electrostatic and nonpolar side-chain interactions between Rap1's HVR residues, lipid, and CAP1 β-sheet domain. The binding was stabilized by the lipid insertion into the β-solenoid whose interior was occupied by nonpolar side chains. This model was reminiscent of the recently solved structure of the PDEδ-K-Ras complex; accordingly, disruptors of this complex, deltarasin, blocked the Rap1-CAP1 interaction. These findings indicate that CAP1 is a geranylgeranyl-binding partner of Rap1.

show abstract

mentioning

confidence: 99%

Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase

Zhang

Cao

Barila

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However several studies suggest that this is not the case. Indeed, even though there is a defect in axonal growth in Rap1 conditional KO mice (Shah et al, 2016), an acute but partial inhibition of Rap1 affects the polarization of multipolar cells towards the CP without an apparent effect on axonal growth (Jossin and Cooper, 2011). Therefore the defect in the orientation of multipolar migration observed is independent of axonal growth.…”

Section: Polarity In Mid To Late Born Neuronsmentioning

confidence: 99%

Neuronal Polarity in the Embryonic Mammalian Cerebral Cortex

Kon

Cossard

Jossin

2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

The cerebral cortex is composed of billions of neurons that can grossly be subdivided into two broad classes: inhibitory GABAergic interneurons and excitatory glutamatergic neurons. The majority of cortical neurons in mammals are the excitatory type and they are the main focus of this review article. Like many of the cells in multicellular organisms, fully differentiated neurons are both morphologically and functionally polarized. However, they go through several changes in polarity before reaching this final mature differentiated state. Neurons are derived from polarized neuronal progenitor/stem cells and their commitment to neuronal fate is decided by cellular and molecular asymmetry during their last division in the neurogenic zone. They migrate from their birthplace using so-called multipolar migration, during which they switch direction of movement several times, and repolarize for bipolar migration when the axon is specified. Therefore, neurons have to break their previous symmetry, change their morphology and adequately respond to polarizing signals during migration in order to reach the correct position in the cortex and start making connections. Finally, the dendritic tree is elaborated and the axon/dendrite morphological polarity is set. Here we will describe the function, establishment and maintenance of polarity during the different developmental steps starting from neural stem cell (NSC) division, neuronal migration and axon specification at embryonic developmental stages.

show abstract

“…Moreover, Rapgef2-cKO mice displayed severe defects in formation of the apical surface structure, which is composed of an assembly of the endfeet of the apical RG fibers linked together by an array of AJs, resulting in earlier detachment and aberrant localization of RGCs around embryonic day (E) 14.5 [11]. Rap1-cKO mice also exhibited almost identical phenotypes [14]. In addition, Rapgef2 and Rap1 are implicated in multipolar-bipolar transition of post-mitotic neurons [5,11,14].…”

mentioning

confidence: 99%

“…Rap1-cKO mice also exhibited almost identical phenotypes [14]. In addition, Rapgef2 and Rap1 are implicated in multipolar-bipolar transition of post-mitotic neurons [5,11,14]. However, little is known about the molecular mechanism underlying these functions of Rapgef2 and Rap1 during cortical development.…”

mentioning

confidence: 99%

Rapgef2, a guanine nucleotide exchange factor for Rap1 small GTPases, plays a crucial role in adherence junction (AJ) formation in radial glial cells through ERK-mediated upregulation of the AJ-constituent protein expression

Farag

Yoshikawa

Maeta

et al. 2017

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Rapgef2 and Rapgef6 define a subfamily of guanine nucleotide exchange factors for Rap1, characterized by possession of the Ras/Rap-associating domains and implicated in the etiology of schizophrenia. We previously found that dorsal telencephalon-specific Rapgef2 conditional knockout mice exhibits severe defects in formation of apical surface adherence junctions (AJs) and localization of radial glial cells (RGCs). In this study, we analyze the underlying molecular mechanism by using primary cultures of RGCs established from the developing cerebral cortex. The results show that Rapgef2-deficient RGCs exhibit a decreased ability of neurosphere formation, morphological changes represented by regression of radial glial (RG) fibers and reduced expression of AJ-constituent proteins such as N-cadherin, zonula occludens-1, E-cadherin and β-catenin. Moreover, siRNA-mediated knockdown of Rapgef2 or Rap1A inhibits the AJ protein expression and RG fiber formation while overexpression of Rapgef2, Rapgef6, Rap1A or Rap1B in Rapgef2-deficient RGCs restores them. Furthermore, Rapgef2-deficient RGCs exhibit a reduction in phosphorylation of extracellular signal-regulated kinase (ERK) leading to downregulation of the expression of c-jun, which is implicated in the AJ protein expression. These results indicate a crucial role of the Rapgef2-Rap1A-ERK-c-jun pathway in regulation of the AJ formation in RGCs.

show abstract

Rap1 GTPases Are Master Regulators of Neural Cell Polarity in the Developing Neocortex

Cited by 33 publications

References 74 publications

Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase

Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase

Neuronal Polarity in the Embryonic Mammalian Cerebral Cortex

Rapgef2, a guanine nucleotide exchange factor for Rap1 small GTPases, plays a crucial role in adherence junction (AJ) formation in radial glial cells through ERK-mediated upregulation of the AJ-constituent protein expression

Contact Info

Product

Resources

About