Microcephaly gene Cenpj regulates axonal growth in cortical neurons through microtubule destabilization. Issue 4 (9th January 2022)

• Record Type: Journal Article
• Authors: Meneses Iack, Pamela; Rayêe, Danielle; Lent, Roberto; Ribeiro‐Resende, Victor Túlio; Garcez, Patrícia P.
• Is Part Of: Journal of neurochemistry. Volume 161:Issue 4(2022)
• Page Start: 320
• Page End: 334
• Publication Date: 2022-01-09
• Subjects: axonal growth -- CENPJ -- cortical neurons -- microcephaly -- microtubule; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.15568
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Neocortex development comprises of a complex series of time‐ and space‐specific processes to generate the typical interconnected six‐layered architecture of adult mammals. Axon growth is required for the proper establishment of cortical circuits. Malformations in axonal growth and pathfinding might lead to severe neuropathologies, such as corpus callosum dysgenesis. Cenpj, a microcephaly gene, encodes a scaffold protein that regulates centrosome biogenesis and microtubule stabilization. During corticogenesis, Cenpj regulates progenitor division and neuronal migration. Since microtubule stabilization is crucial for axon extension, we investigated the role of Cenpj in axon growth during cortical development in a mouse model. Through loss‐ and gain‐of‐function assays ex vivo and in utero, we quantified callosal axonal length, branching, and growth cone size compared to controls. We observed that silencing Cenpj results in an increased axonal length. Ex vivo, we assessed the number of branches, the area of growth cones and the stability of microtubules. In silenced Cenpj axons, there were more branches, larger growth cone area, and more stable microtubules. Rescue experiments confirmed that neurons present axonal length comparable to controls. Here we propose that Cenpj regulates axon growth by destabilizing microtubules during cortical development. Finally, our findings suggest that Cenpj might be a novel target for axonal regeneration. Abstract : Here, we have examined the role of Cenpj, a microcephaly gene, in axonogenesis. Aspects of axon growth after gain and loss of function of Cenpj during corpus callosum development in mouse model were analysed using in utero and ex vivo electroporation. The results suggest that Cenpj regulates axon growth by destabilizing microtubules through its domain PN2‐3 during cortical development. Together, this work sheds new light in the understanding of molecular mechanisms of axon growth in cortical development which could be also relevant for axonal regeneration.