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Regulation of cerebral cortex development by Rho GTPases: insights from in vivo studies.

Azzarelli R, Kerloch T, Pacary E - Front Cell Neurosci (2015)

Bottom Line: Cortical neuron development is a multiphasic process characterized by sequential steps of neural progenitor proliferation, cell cycle exit, neuroblast migration and neuronal differentiation.This series of events requires an extensive and dynamic remodeling of the cell cytoskeleton at each step of the process.As major regulators of the cytoskeleton, the family of small Rho GTPases has been shown to play essential functions in cerebral cortex development.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, University of Cambridge Cambridge, UK.

ABSTRACT
The cerebral cortex is the site of higher human cognitive and motor functions. Histologically, it is organized into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection neurons and inhibitory interneurons. The stereotyped cellular distribution of cortical neurons is crucial for the formation of functional neural circuits and it is predominantly established during embryonic development. Cortical neuron development is a multiphasic process characterized by sequential steps of neural progenitor proliferation, cell cycle exit, neuroblast migration and neuronal differentiation. This series of events requires an extensive and dynamic remodeling of the cell cytoskeleton at each step of the process. As major regulators of the cytoskeleton, the family of small Rho GTPases has been shown to play essential functions in cerebral cortex development. Here we review in vivo findings that support the contribution of Rho GTPases to cortical projection neuron development and we address their involvement in the etiology of cerebral cortex malformations.

No MeSH data available.


Related in: MedlinePlus

The classical Rho GTPase cycle and the main pathways regulated by active RhoA (in blue), Rac1 (in green), and Cdc42 (in purple). Guanine nucleotide-exchange factors (GEFs) activate Rho GTPases by promoting the release of GDP and the binding of GTP whereas GTPase-activating proteins (GAPs) inactivate Rho GTPases by increasing the intrinsic GTPase activity of Rho proteins. Guanine nucleotide-dissociation inhibitors (GDIs) sequester RhoGTPase in their inactive state and protect them from degradation. In their active form, Rho GTPases can bind to different effector molecules. Dia: Diaphanous-related formins; ROCK: Rho Kinase; MLCP: myosin light chain phosphatase; MLC: myosin light chain; MLCK: myosin light chain kinase; WAVE: Wiskott–Aldrich syndrome protein family verprolin homolog; Arp2/3: actin-related proteins 2 and 3; PAK: p21-activated kinases; LIMK: Lin-11, Isl-1, and Mec-3 kinase; WASP: Wiskott-Aldrich syndrome protein.
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Figure 2: The classical Rho GTPase cycle and the main pathways regulated by active RhoA (in blue), Rac1 (in green), and Cdc42 (in purple). Guanine nucleotide-exchange factors (GEFs) activate Rho GTPases by promoting the release of GDP and the binding of GTP whereas GTPase-activating proteins (GAPs) inactivate Rho GTPases by increasing the intrinsic GTPase activity of Rho proteins. Guanine nucleotide-dissociation inhibitors (GDIs) sequester RhoGTPase in their inactive state and protect them from degradation. In their active form, Rho GTPases can bind to different effector molecules. Dia: Diaphanous-related formins; ROCK: Rho Kinase; MLCP: myosin light chain phosphatase; MLC: myosin light chain; MLCK: myosin light chain kinase; WAVE: Wiskott–Aldrich syndrome protein family verprolin homolog; Arp2/3: actin-related proteins 2 and 3; PAK: p21-activated kinases; LIMK: Lin-11, Isl-1, and Mec-3 kinase; WASP: Wiskott-Aldrich syndrome protein.

Mentions: Like other small GTP-binding proteins of the Ras superfamily, most Rho GTPases cycle between GTP (active) and GDP (inactive)—bound states. The GDP/GTP cycle is promoted by the activity of two classes of molecules, guanine nucleotide exchanging factors (GEFs) and GTPase activating proteins (GAPs). GEFs facilitate the exchange of GDP with GTP, resulting in protein activation. GAPs instead stimulate the intrinsic enzymatic activity of the GTPases, which promotes hydrolysis of GTP into GDP. GAP activity therefore ends the cycle and returns the GTPases in their inactive state (Bos et al., 2007) (Figure 2). Over 80 GEFs and more than 70 GAPs have been reported, suggesting that Rho GTPase regulation is complex. In addition, Rho GTPases can bind to proteins known as guanine-nucleotide dissociation inhibitors (GDIs). RhoGDIs sequester RhoGTPase in their inactive state and protect them from degradation (Boulter et al., 2010) (Figure 2). When bound to GTP, Rho GTPases exhibit the correct structural conformation to interact with effectors and initiate downstream signaling to regulate actin and microtubule components of the cytoskeleton (Jaffe and Hall, 2005) (Figure 2). However, some members of the family do not follow this classical scheme of activation and are described as atypical. These atypical Rho GTPases are predominantly GTP bound, owing either to aminoacid substitutions at residues that are crucial for GTPase activity (for example in Rnd proteins) or owing to increased nucleotide exchange (for example in RhoU). Therefore, their expression, localization, stability and phosphorylation control their activity rather than the GDP/GTP switch (Aspenstrom et al., 2007) (Figure 1).


Regulation of cerebral cortex development by Rho GTPases: insights from in vivo studies.

Azzarelli R, Kerloch T, Pacary E - Front Cell Neurosci (2015)

The classical Rho GTPase cycle and the main pathways regulated by active RhoA (in blue), Rac1 (in green), and Cdc42 (in purple). Guanine nucleotide-exchange factors (GEFs) activate Rho GTPases by promoting the release of GDP and the binding of GTP whereas GTPase-activating proteins (GAPs) inactivate Rho GTPases by increasing the intrinsic GTPase activity of Rho proteins. Guanine nucleotide-dissociation inhibitors (GDIs) sequester RhoGTPase in their inactive state and protect them from degradation. In their active form, Rho GTPases can bind to different effector molecules. Dia: Diaphanous-related formins; ROCK: Rho Kinase; MLCP: myosin light chain phosphatase; MLC: myosin light chain; MLCK: myosin light chain kinase; WAVE: Wiskott–Aldrich syndrome protein family verprolin homolog; Arp2/3: actin-related proteins 2 and 3; PAK: p21-activated kinases; LIMK: Lin-11, Isl-1, and Mec-3 kinase; WASP: Wiskott-Aldrich syndrome protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4285737&req=5

Figure 2: The classical Rho GTPase cycle and the main pathways regulated by active RhoA (in blue), Rac1 (in green), and Cdc42 (in purple). Guanine nucleotide-exchange factors (GEFs) activate Rho GTPases by promoting the release of GDP and the binding of GTP whereas GTPase-activating proteins (GAPs) inactivate Rho GTPases by increasing the intrinsic GTPase activity of Rho proteins. Guanine nucleotide-dissociation inhibitors (GDIs) sequester RhoGTPase in their inactive state and protect them from degradation. In their active form, Rho GTPases can bind to different effector molecules. Dia: Diaphanous-related formins; ROCK: Rho Kinase; MLCP: myosin light chain phosphatase; MLC: myosin light chain; MLCK: myosin light chain kinase; WAVE: Wiskott–Aldrich syndrome protein family verprolin homolog; Arp2/3: actin-related proteins 2 and 3; PAK: p21-activated kinases; LIMK: Lin-11, Isl-1, and Mec-3 kinase; WASP: Wiskott-Aldrich syndrome protein.
Mentions: Like other small GTP-binding proteins of the Ras superfamily, most Rho GTPases cycle between GTP (active) and GDP (inactive)—bound states. The GDP/GTP cycle is promoted by the activity of two classes of molecules, guanine nucleotide exchanging factors (GEFs) and GTPase activating proteins (GAPs). GEFs facilitate the exchange of GDP with GTP, resulting in protein activation. GAPs instead stimulate the intrinsic enzymatic activity of the GTPases, which promotes hydrolysis of GTP into GDP. GAP activity therefore ends the cycle and returns the GTPases in their inactive state (Bos et al., 2007) (Figure 2). Over 80 GEFs and more than 70 GAPs have been reported, suggesting that Rho GTPase regulation is complex. In addition, Rho GTPases can bind to proteins known as guanine-nucleotide dissociation inhibitors (GDIs). RhoGDIs sequester RhoGTPase in their inactive state and protect them from degradation (Boulter et al., 2010) (Figure 2). When bound to GTP, Rho GTPases exhibit the correct structural conformation to interact with effectors and initiate downstream signaling to regulate actin and microtubule components of the cytoskeleton (Jaffe and Hall, 2005) (Figure 2). However, some members of the family do not follow this classical scheme of activation and are described as atypical. These atypical Rho GTPases are predominantly GTP bound, owing either to aminoacid substitutions at residues that are crucial for GTPase activity (for example in Rnd proteins) or owing to increased nucleotide exchange (for example in RhoU). Therefore, their expression, localization, stability and phosphorylation control their activity rather than the GDP/GTP switch (Aspenstrom et al., 2007) (Figure 1).

Bottom Line: Cortical neuron development is a multiphasic process characterized by sequential steps of neural progenitor proliferation, cell cycle exit, neuroblast migration and neuronal differentiation.This series of events requires an extensive and dynamic remodeling of the cell cytoskeleton at each step of the process.As major regulators of the cytoskeleton, the family of small Rho GTPases has been shown to play essential functions in cerebral cortex development.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, University of Cambridge Cambridge, UK.

ABSTRACT
The cerebral cortex is the site of higher human cognitive and motor functions. Histologically, it is organized into six horizontal layers, each containing unique populations of molecularly and functionally distinct excitatory projection neurons and inhibitory interneurons. The stereotyped cellular distribution of cortical neurons is crucial for the formation of functional neural circuits and it is predominantly established during embryonic development. Cortical neuron development is a multiphasic process characterized by sequential steps of neural progenitor proliferation, cell cycle exit, neuroblast migration and neuronal differentiation. This series of events requires an extensive and dynamic remodeling of the cell cytoskeleton at each step of the process. As major regulators of the cytoskeleton, the family of small Rho GTPases has been shown to play essential functions in cerebral cortex development. Here we review in vivo findings that support the contribution of Rho GTPases to cortical projection neuron development and we address their involvement in the etiology of cerebral cortex malformations.

No MeSH data available.


Related in: MedlinePlus