Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin.
Neocortical neurons have highly branched dendritic trees that are essential for their function. Indeed, defects in dendritic arborization are associated with human neurodevelopmental disorders. The molecular mechanisms regulating dendritic arbor complexity, however, are still poorly understood. Here, we uncover the molecular basis for the regulation of dendritic branching during cortical development. We show that during development, dendritic branching requires post-mitotic suppression of the RhoGTPase Cdc42. By generating genetically modified mice, we demonstrate that this is catalyzed in vivo by the novel Cdc42-GAP NOMA-GAP. Loss of NOMA-GAP leads to decreased neocortical volume, associated specifically with profound oversimplification of cortical dendritic arborization and hyperactivation of Cdc42. Remarkably, dendritic complexity and cortical thickness can be partially restored by genetic reduction of post-mitotic Cdc42 levels. Furthermore, we identify the actin regulator cofilin as a key regulator of dendritic complexity in vivo. Cofilin activation during late cortical development depends on NOMA-GAP expression and subsequent inhibition of Cdc42. Strikingly, in utero expression of active cofilin is sufficient to restore postnatal dendritic complexity in NOMA-GAP-deficient animals. Our findings define a novel cell-intrinsic mechanism to regulate dendritic branching and thus neuronal complexity in the cerebral cortex.
Neurocure Excellence Cluster, Institute of Cell and Neurobiology, Charité Universitätsmedizin Berlin, Germany. marta.rosario@charite.de
Marta
M
Rosário
Steffen
S
Schuster
René
R
Jüttner
Srinivas
S
Parthasarathy
Victor
V
Tarabykin
Walter
W
Birchmeier
D051339:Actin Depolymerizing Factors / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D019579:Neocortex / Q000254:growth & development* / Q000378:metabolism*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
D051339:Actin Depolymerizing Factors; D020690:GTPase-Activating Proteins; C475478:TCGAP protein, mouse; D020764:cdc42 GTP-Binding Protein