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Synaptic structural plasticity, the expansion of dendritic spines in response to synaptic stimulation, is essential for experience-dependent plasticity and is driven by branched actin polymerization. The WAVE regulatory complex (WRC) is confined to nanodomains at the postsynaptic membrane where it catalyzes actin polymerization. As the netrin/RGM receptor Neogenin is a critical regulator of the WRC, its nanoscale organization may be an important determinant of WRC nanoarchitecture and function. Using super-resolution microscopy, we reveal that Neogenin is highly organized on the spine membrane at the nanoscale level. We show that Neogenin binding to the WRC promotes co-clustering into nanodomains in response to brain-derived neurotrophic factor (BDNF), indicating that nanoclustering occurs in response to synaptic stimulation. Disruption of Neogenin/WRC binding not only prevents BDNF-mediated actin remodeling but also inhibits BDNF-induced calcium signaling. We conclude that the assembly of Neogenin/WRC nanodomains is a prerequisite for BDNF-mediated structural and synaptic plasticity., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Structural plasticity, the ability of dendritic spines to change their volume in response to synaptic stimulation, is an essential determinant of synaptic strength and long-term potentiation (LTP), the proposed cellular substrate for learning and memory. Branched actin polymerization is a major force driving spine enlargement and sustains structural plasticity. The WAVE Regulatory Complex (WRC), a pivotal branched actin regulator, controls spine morphology and therefore structural plasticity. However, the molecular mechanisms that govern WRC activation during spine enlargement are largely unknown. Here we identify a critical role for Neogenin and its ligand RGMa (Repulsive Guidance Molecule a) in promoting spine enlargement through the activation of WRC-mediated branched actin remodeling. We demonstrate that Neogenin regulates WRC activity by binding to the highly conserved Cyfip/Abi binding pocket within the WRC. We find that after Neogenin or RGMa depletion, the proportions of filopodia and immature thin spines are dramatically increased, and the number of mature mushroom spines concomitantly decreased. Wildtype Neogenin, but not Neogenin bearing mutations in the Cyfip/Abi binding motif, is able to rescue the spine enlargement defect. Furthermore, Neogenin depletion inhibits actin polymerization in the spine head, an effect that is not restored by the mutant. We conclude that RGMa and Neogenin are critical modulators of WRC-mediated branched actin polymerization promoting spine enlargement. This study also provides mechanistic insight into Neogenin's emerging role in LTP induction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sempert, Shohayeb, Lanoue, O’Brien, Flores and Cooper.)

Neural stem cells must rapidly adapt their transcriptional activity to the ever-changing embryonic environment. Currently, we have a limited understanding of how key transcription factors such as Pax6 are modulated at the protein level. In a recent issue of the JBC, Dong et al identified a novel posttranslational regulatory mechanism in which Kat2a-mediated lysine acetylation on Pax6 leads to its ubiquitination and ultimately its degradation via the proteasome pathway, thereby determining whether neural stem cells undergo proliferation or neuronal differentiation., Competing Interests: Conflicts of interest The authors declare they have no competing interests with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Homozygous nonsense mutations in CEP55 are associated with several congenital malformations that lead to perinatal lethality suggesting that it plays a critical role in regulation of embryonic development. CEP55 has previously been studied as a crucial regulator of cytokinesis, predominantly in transformed cells, and its dysregulation is linked to carcinogenesis. However, its molecular functions during embryonic development in mammals require further investigation. We have generated a Cep55 knockout (Cep55-/-) mouse model which demonstrated preweaning lethality associated with a wide range of neural defects. Focusing our analysis on the neocortex, we show that Cep55-/- embryos exhibited depleted neural stem/progenitor cells in the ventricular zone as a result of significantly increased cellular apoptosis. Mechanistically, we demonstrated that Cep55-loss downregulates the pGsk3β/β-Catenin/Myc axis in an Akt-dependent manner. The elevated apoptosis of neural stem/progenitors was recapitulated using Cep55-deficient human cerebral organoids and we could rescue the phenotype by inhibiting active Gsk3β. Additionally, we show that Cep55-loss leads to a significant reduction of ciliated cells, highlighting a novel role in regulating ciliogenesis. Collectively, our findings demonstrate a critical role of Cep55 during brain development and provide mechanistic insights that may have important implications for genetic syndromes associated with Cep55-loss., Competing Interests: The authors have declared that no competing interests exist.

One paramount challenge for neuroscientists over the past century has been to identify the embryonic origins of the enormous diversity of cortical neurons found in the adult human neocortex and to unravel the developmental processes governing their emergence. In all mammals, including humans, the radial glia lining the ventricles of the embryonic telencephalon, more recently reclassified as apical radial glia (aRGs), have been identified as the neural progenitors giving rise to all excitatory neurons and inhibitory interneurons of the six-layered cortex. In this review, we explore the fundamental molecular and cellular mechanisms that regulate aRG function and the generation of neuronal diversity in the dorsal telencephalon. We survey the key structural features essential for the retention of the highly polarized aRG morphology and therefore impose aRG identity after cytokinesis. We discuss how these structures and associated molecular signaling complexes influence aRG proliferative capacity and the decision to undergo proliferative self-renewing symmetric or neurogenic asymmetric divisions. We also explore the intriguing and complex question of how the extensive neuronal diversity within the adult neocortex arises from the small aRG population located within the cortical proliferative zone. We further highlight the recent clonal lineage tracing and single-cell transcriptomic profiling studies providing compelling evidence that individual neuronal identity emerges as a consequence of exposure to temporally regulated extrinsic cues which coordinate waves of transcriptional activity that evolve over time to drive neuronal commitment and maturation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)