The journal of neuroscience : the official journal of the Society for Neuroscience.

Neural stem and progenitor cells have a central role in the development and evolution of the mammalian neocortex. In this review, we first provide a set of criteria to classify the various types of cortical stem and progenitor cells. We then discuss the issue of cell polarity, as well as specific subcellular features of these cells that are relevant for their modes of division and daughter cell fate. In addition, cortical stem and progenitor cell behavior is placed into a tissue context, with consideration of extracellular signals and cell-cell interactions. Finally, the differences across species regarding cortical stem and progenitor cells are dissected to gain insight into key developmental and evolutionary mechanisms underlying neocortex expansion.

The Cell Biology of Neurogenesis: Toward an Understanding of the Development and Evolution of the Neocortex

https://www.cell.com/neuron/pdf/S0896-6273(14)00917-9.pdf

Axonal transport: cargo-specific mechanisms of motility and regulation

Malformations of cortical development are common causes of developmental delay and epilepsy. Some patients have early, severe neurological impairment, but others have epilepsy or unexpected deficits that are detectable only by screening. The rapid evolution of molecular biology, genetics, and imaging has resulted in a substantial increase in knowledge about the development of the cerebral cortex and the number and types of malformations reported. Genetic studies have identified several genes that might disrupt each of the main stages of cell proliferation and specification, neuronal migration, and late cortical organisation. Many of these malformations are caused by de-novo dominant or X-linked mutations occurring in sporadic cases. Genetic testing needs accurate assessment of imaging features, and familial distribution, if any, and can be straightforward in some disorders but requires a complex diagnostic algorithm in others. Because of substantial genotypic and phenotypic heterogeneity for most of these genes, a comprehensive analysis of clinical, imaging, and genetic data is needed to properly define these disorders. Exome sequencing and high-field MRI are rapidly modifying the classification of these disorders.

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Malformations of cortical development: clinical features and genetic causes

Lysosomes have been classically considered terminal degradative organelles, but in recent years they have been found to participate in many other cellular processes, including killing of intracellular pathogens, antigen presentation, plasma membrane repair, cell adhesion and migration, tumor invasion and metastasis, apoptotic cell death, metabolic signaling and gene regulation In addition, lysosome dysfunction has been shown to underlie not only rare lysosome storage disorders but also more common diseases, such as cancer and neurodegeneration The involvement of lysosomes in most of these processes is now known to depend on the ability of lysosomes to move throughout the cytoplasm Here, we review recent findings on the mechanisms that mediate the motility and positioning of lysosomes, and the importance of lysosome dynamics for cell physiology and pathology

Mechanisms and functions of lysosome positioning

The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.

/pdf/mutations-in-tubg1-dync1h1-kif5c-and-kif2a-cause-22x1c3d875.pdf

Mutations in TUBG1 , DYNC1H1 , KIF5C and KIF2A cause malformations of cortical development and microcephaly

/pdf/erratum-mutations-in-tubg1-dync1h1-kif5c-and-kif2a-cause-2cy42u7oqi.pdf

Erratum: Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly (Nature Genetics (2013) 45 (639-647))

Franscesca Darra

Papers

Mutations in TUBG1 , DYNC1H1 , KIF5C and KIF2A cause malformations of cortical development and microcephaly

Erratum: Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly (Nature Genetics (2013) 45 (639-647))