N-cofilin is associated with neuronal migration disorders and cell cycle control in the cerebral cortex

Bellenchi, Gian Carlo; Gurniak, Christine B.; Perlas, Emerald; Middei, Silvia; Ammassari–Teule, Martine; Witke, Walter

doi:10.1101/gad.434307

Cited by 179 publications

(194 citation statements)

References 55 publications

(66 reference statements)

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“…Because it is implicated in several processes that are crucial for cortical development, it is likely that some of the genes regulated by ARX may be potential candidates for neurological diseases such as epilepsy, mental retardation, schizophrenia, dyslexia, autism, and cortical malformations (such as lissencephaly and microcephaly or macrocephaly). Interestingly, a recent study has shown that mutant mice for N-cofilin, an F-actindepolymerizing factor, display impaired radial and tangential migration, as well as an increased cell cycle exit of neuronal progenitors in the VZ (Bellenchi et al, 2007). These results, similar to what we have shown for ARX, demonstrate that mutations affecting regulators of the actin cytoskeleton contribute to the pathology of cortex development, and open new prospects concerning the pathways regulated by ARX.…”

Section: Pathophysiology Of Phenotypes Resulting From Arx Mutationssupporting

confidence: 75%

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Friocourt¹,

Kanatani²,

Tabata³

et al. 2008

J. Neurosci.

117

106

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The aristaless-related homeobox (ARX) gene has been implicated in a wide spectrum of disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of X-linked mental retardation without apparent brain abnormalities. To better understand its role in corticogenesis, we used in utero electroporation to knock down or overexpress ARX. We show here that targeted inhibition of ARX causes cortical progenitor cells to exit the cell cycle prematurely and impairs their migration toward the cortical plate. In contrast, ARX overexpression increases the length of the cell cycle. In addition, we report that RNA interferencemediated inactivation of ARX prevents cells from acquiring multipolar morphology in the subventricular and intermediate zones, resulting in decreased neuronal motility. In contrast, ARX overexpression appears to promote the development of tangentially oriented processes of cells in the subventricular and intermediate zones and affects radial migration of pyramidal neurons. We also demonstrate that the level of ARX expression is important for tangential migration of GABA-containing interneurons, because both inactivation and overexpression of the gene impair their migration from the ganglionic eminence. However, our data suggest that ARX is not directly involved in GABAergic cell fate specification. Overall, these results identify multiple and distinct cell-autonomous roles for ARX in corticogenesis.

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Section: Pathophysiology Of Phenotypes Resulting From Arx Mutationssupporting

confidence: 75%

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Friocourt¹,

Kanatani²,

Tabata³

et al. 2008

J. Neurosci.

117

106

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“…It has been shown that the inability of cortical neurons to exit from the multipolar phase of radial migration results in abnormal dendritic development of pyramidal neurons in the postnatal cerebral cortex (21,22). Interestingly, previous studies revealed a role for TBC1D24 in neurite outgrowth in vitro (7,8,10), and we found that TBC1D24 expression also increased during postnatal development (Fig.…”

Section: Tbc1d24 Knockdown Alters Dendritic Arborization and Glutamatsupporting

confidence: 63%

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

Falace

Buhler

Fadda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development.dendritogenesis | synaptogenesis | epileptic encephalopathies | gene | RNA interferenceT he mammalian cerebral cortex is a multilayered structure derived from cells of the neural tube (1). Cortical projection neurons are generated from proliferating progenitor cells located in the ventricular zone (VZ) adjacent to the lateral ventricle (2). After their final mitotic division, the majority of neurons migrate radially, along radial glia fibers, from the VZ toward the pial surface, where each successive generation passes one another and settles in an inside-out pattern within the cortical plate (CP) (3, 4). When neurons reach their final destination, they stop migrating and order themselves into specific "architectonic" patterns, according to a complex signaling pathway, guiding cells to the correct location in the brain (5). Overall, these steps lead to the formation of a six-layered cortex that plays a key role in cognitive processes. It is therefore not surprising that disruption of early cortical development causes severe neurological conditions usually featuring intellectual disabilities (IDs) and epilepsy, which may be associated with brain malformations (6).Over the past decades, advances in our understanding of the genetics of ID and epilepsy have revolutionized the diagnostic and the clinical approach to these disorders, and an increasing number of pathogenic gene mutations have been identified. TBC1D24 is a novel epilepsy-related gene mutated in different autosomal recessive forms of early-onset epilepsy, which can be accompanied by variable degrees of ID (7-11). The TBC1D24 gene encodes a protein of 553 aa that contains a Tre2/Bub2/Cdc16 (TBC) domain, shared by Rab GTPase-activating proteins (Rab-GAPs) and a TLDc domain of unknown function (8). The TBC1D24 protein is expressed in the brain and interacts with the ADP ribosylation factor (ARF) 6, a small GTP-binding prot...

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“…We noted altered behavior in ACC mice, which lack ADF systemically and n-cofilin specifically in the adult telencephalon (16,20). The mice appeared more active compared with controls or single mutants, for example, on opening of the cage and removal of nest material (Supplemental Video S1 in Supplement 2).…”

Section: Hyperlocomotion Reduced Response Habituation and Impaired mentioning

confidence: 97%

“…Actin depolymerizing proteins of the actin depolymerizing factor (ADF)/cofilin family are essential regulators of actin dynamics (15). Two family members, ADF and n-cofilin, are highly abundant in the adult brain and present in excitatory synapses (16)(17)(18). Analyses of gene-targeted mice revealed the relevance of n-cofilin for postsynaptic plasticity, learning, and anxiety (19,20).…”

mentioning

confidence: 99%

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

Zimmermann

Jene

Wolf

et al. 2015

Biological Psychiatry

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BACKGROUND: Actin depolymerizing proteins of the actin depolymerizing factor (ADF)/cofilin family are essential for actin dynamics, which is critical for synaptic function. Two ADF/cofilin family members, ADF and n-cofilin, are highly abundant in the brain, where they are present in excitatory synapses. Previous studies demonstrated the relevance of n-cofilin for postsynaptic plasticity, associative learning, and anxiety. These studies also suggested overlapping functions for ADF and n-cofilin. METHODS: We performed pharmacobehavioral, electrophysiologic, and electron microscopic studies on ADF and n-cofilin single mutants and double mutants (named ACC mice) to characterize the importance of ADF/cofilin activity for synapse physiology and mouse behavior. RESULTS: The ACC mice, but not single mutants, exhibited hyperlocomotion, impulsivity, and impaired working memory. Hyperlocomotion and impulsive behavior were reversed by methylphenidate, a psychostimulant commonly used for the treatment of attention-deficit/hyperactivity disorder (ADHD). Also, ACC mice displayed a disturbed morphology of striatal excitatory synapses, accompanied by strongly increased glutamate release. Blockade of dopamine or glutamate transmission resulted in normal locomotion. CONCLUSIONS: Our study reveals that ADHD can result from a disturbed balance between excitation and inhibition in striatal circuits, providing novel insights into the mechanisms underlying this neurobehavioral disorder. Our results link actin dynamics to ADHD, suggesting that mutations in actin regulatory proteins may contribute to the etiology of ADHD in humans.

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N-cofilin is associated with neuronal migration disorders and cell cycle control in the cerebral cortex

Cited by 179 publications

References 55 publications

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

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