FLNA regulates neuronal maturation by modulating RAC1-Cofilin activity in the developing cortex

Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene – encoding an actin-binding protein - and patients often de...

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Published in:	Neurobiology of disease Vol. 198; p. 106558
Main Authors:	Falace, Antonio, Corbieres, Lea, Palminha, Catia, Guarnieri, Fabrizia Claudia, Schaller, Fabienne, Buhler, Emmanuelle, Tuccari di San Carlo, Clara, Montheil, Aurelie, Watrin, Françoise, Manent, Jean Bernard, Represa, Alfonso, de Chevigny, Antoine, Pallesi-Pocachard, Emilie, Cardoso, Carlos
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-08-2024 Elsevier
Subjects:	Animal model Brain development Dendritogenesis -neurodevelopmental disorders Life Sciences Neuronal maturation Neurons and Cognition S3A GTP ADF cKO FMR1 Brain development PNH E14.5 PTI-25 CDP DsRed PBD IUE mTOR RAC1 flox LoxP PSD BCA CALNL Q61L TSC FCD CAG ARHGA24 Tbr1 SDS-PAGE T17N MEK F-actin rpS6 Xq28 CRE GAP ND1 SEM mTORC1 ERK Animal model Neuronal maturation NeuroD1 RIPA GFP Rheb ANOVA FLNA Shank3B P6 GST MCD Dendritogenesis -neurodevelopmental disorders PAC P15 LIMK FingR
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Summary:	Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene – encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flnaflox/flox mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations. •FLNA regulates dendritogenesis and spinogenesis in vivo.•FLNA modulates RAC1-Cofilin signaling in cortical projecting neurons.•FLNA exerts its role through the interaction with ARHGAP24.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0969-9961 1095-953X 1095-953X
DOI:	10.1016/j.nbd.2024.106558