VPS35 deficiency in the embryonic cortex leads to prenatal cell loss and abnormal development of axonal connectivity

• Published in: Molecular and cellular neuroscience Vol. 120; p. 103726
• Main Authors: Roque, Micaela, Alves Rodrigues de Souza, Diego, Rangel-Sosa, Martha M., Altounian, Mike, Hocine, Mélanie, Deloulme, Jean-Christophe, Barbier, Emmanuel L., Mann, Fanny, Chauvet, Sophie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2022; Elsevier
• Subjects: 3D imaging; Axon guidance; Cell death; DTI; Life Sciences; Mice; Neurogenesis; Retromer; VPS35; 3D imaging; Cell death; DTI; VPS35; Mice; Axon guidance; Neurogenesis; Retromer
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2022.103726

VPS35 is a core component of the retromer complex involved in familial forms of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In mice, VPS35 is expressed during early brain development. However, previous studies have reported that VPS35 activity is largely dispensable for normal neuronal development and initial elaboration of axonal projections. Here, we evaluated the role of VPS35 in the mouse embryonic brain using two Cre-driver lines that remove Vps35 from the cortex at different prenatal stages. We found that Vps35 mutant mice displayed microcephaly and decreased cortical thickness from the embryonic stages to adulthood. VPS35 also regulates cortical development by affecting a subpopulation of neural progenitor cells and the survival of postmitotic neurons. In addition, we showed that a lack of VPS35 leads to hypoplasia and misrouting of several axonal projections, including the anterior commissure and fornix. Furthermore, VPS35 deficiency impairs the non-autonomous development of thalamocortical axons (TCAs), which show severe disruption of innervation and terminal arborization in the cortex. Together, these data demonstrate that VPS35 plays a greater role in embryonic development of the mammalian brain than it was previously thought. •The retromer component VPS35 is required during embryonic development of the mouse brain.•VPS35 regulates cortical progenitor cell numbers and survival of newborn neurons•VPS35 plays a non-autonomous function in the development of thalamocortical projections.•Vps35 controls the growth and guidance of cortical efferent projections.