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

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.

PlexinD1 and Sema3E determine laminar positioning of heterotopically projecting callosal neurons.

The corpus callosum is the largest bundle of commissural fibres that transfer information between the two cerebral hemispheres. Callosal projection neurons (CPNs) are a diverse population of pyramidal neurons within the neocortex that mainly interconnect homotopic regions of the opposite cortices. Nevertheless, some CPNs are involved in heterotopic projections between distinct cortical areas or to subcortical regions such as the striatum. In this study, we showed that the axon guidance receptor PlexinD1 is expressed by a large proportion of heterotopically projecting CPNs in layer 5A of the primary somatosensory (S1) and motor (M1) areas. Retrograde tracing of M1 CPNs projecting to the contralateral striatum revealed the presence of ectopic neurons aberrantly located in layers 2/3 of Plxnd1 and Sema3e mutant cortices. These results showed that Sema3E/PlexinD1 signalling controls the laminar distribution of heterotopically projecting CPNs.

An Elastin-Derived Composite Matrix for Enhanced Vascularized and Innervated Bone Tissue Reconstruction: From Material Development to Preclinical Evaluation.

Despite progress in bone tissue engineering, reconstruction of large bone defects remains an important clinical challenge. Here, a biomaterial designed to recruit bone cells, endothelial cells, and neuronal fibers within the same matrix is developed, enabling bone tissue regeneration. The bioactive matrix is based on modified elastin-like polypeptides (ELPs) grafted with laminin-derived adhesion peptides IKVAV and YIGSR, and the SNA15 peptide for retention of hydroxyapatite (HA) particles. The composite matrix shows suitable porosity, interconnectivity, biocompatibility for endothelial cells, and the ability to support neurites outgrowth by sensory neurons. Subcutaneous implantation leads to the formation of osteoid tissue, characterized by the presence of bone cells, vascular networks, and neuronal structures, while minimizing inflammation. Using a rat femoral condyle defect model, longitudinal micro-CT analysis is performed, which demonstrates a significant increase in the volume of mineralized tissue when using the ELP-based matrix compared to empty defects and a commercially available control (Collapat). Furthermore, visible blood vessel networks and nerve fibers are observed within the lesions after a period of two weeks. By incorporating multiple key components that support cell growth, mineralization, and tissue integration, this ELP-based composite matrix provides a holistic and versatile solution to enhance bone tissue regeneration.