Neurologic phenotype of Schimke immuno-osseous dysplasia and neurodevelopmental expression of SMARCAL1

Schimke immuno-osseous dysplasia (OMIM 242900) is an uncommon autosomal-recessive multisystem disease caused by mutations in SMARCAL1 (swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1), a gene encoding a putative chromatin remodeling protein. Neurologic manifestations identified to date relate to enhanced atherosclerosis and cerebrovascular disease. Based on a clinical survey, we determined that half of Schimke immuno-osseous dysplasia patients have a small head circumference, and 15% have social, language, motor, or cognitive abnormalities. Postmortem examination of 2 Schimke immuno-osseous dysplasia patients showed low brain weights and subtle brain histologic abnormalities suggestive of perturbed neuron-glial migration such as heterotopia, irregular cortical thickness, incomplete gyral formation, and poor definition of cortical layers. We found that SMARCAL1 is highly expressed in the developing and adult mouse and human brain, including neural precursors and neuronal lineage cells. These observations suggest that SMARCAL1 deficiency may influence brain development and function in addition to its previously recognized effect on cerebral circulation

In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Features of Embryonic AspM Expressing Cells

Radial Glia (RG) cells constitute the major population of neural progenitors of the mouse developing brain. These cells are located in the ventricular zone (VZ) of the cerebral cortex and during neurogenesis they support the generation of cortical neurons. Later on, during brain maturation, RG cells give raise to glial cells and supply the adult mouse brain of Neural Stem Cells (NSC). Here we used a novel transgenic mouse line expressing the CreERT2 under the control of AspM promoter to monitor the progeny of an early cohort of RG cells during neurogenesis and in the post natal brain. Long term fate mapping experiments demonstrated that AspM-expressing RG cells are multi-potent, as they can generate neurons, astrocytes and oligodendrocytes of the adult mouse brain. Furthermore, AspM descendants give also rise to proliferating progenitors in germinal niches of both developing and post natal brains. In the latter –i.e. the Sub Ventricular Zone- AspM descendants acquired several feature of neural stem cells, including the capability to generate neurospheres in vitro. We also performed the selective killing of these early progenitors by using a Nestin-GFPflox-TK allele. The forebrain specific loss of early AspM expressing cells caused the elimination of most of the proliferating cells of brain, a severe derangement of the ventricular zone architecture, and the impairment of the cortical lamination. We further demonstrated that AspM is expressed by proliferating cells of the adult mouse SVZ that can generate neuroblasts fated to become olfactory bulb neurons

IGF-I protects cortical neurons against ceramide-induced apoptosis via activation of the PI-3K/Akt and ERK pathways; is this protection independent of CREB and Bcl-2?

Current understanding of IGF-I-mediated neuroprotection implies the activation of phosphatidylinositol-3-kinase (PI-3K), which leads to the activation of Akt/Protein Kinase B. In non-neuronal cells, Akt phosphorylates and activates the transcription factor CREB, implicated in the transcription of the anti-apoptotic bcl-2 gene. This paper further analyses the anti-apoptotic IGF-I action in neurons. We show that IGF-I protects cortical neurons against ceramide-induced apoptosis. Ceramide decreases Akt phosphorylation during apoptotic process whereas a simultaneous treatment with IGF-I increases Akt phosphorylation. Analysis of the signal transduction pathways revealed that IGF-I induces CREB phosphorylation via PI-3K and ERK, whereas simultaneous ceramide and IGF-I treatment decreases CREB phosphorylation. Although an overexpression of Bcl-2 protects cortical neurons against ceramide-induced apoptosis, our data indicate that the Bcl-2 protein level is not modulated during IGF-I, ceramide and/or LY294002 treatment. In consequence, we demonstrated that IGF protects neurons against ceramide-induced apoptosis and that IGF-I protection involves the PI-3K/Akt and ERK pathways; this protection may be independent of CREB and Bcl-2

E-Cadherin regulates neural stem cell self-renewal

E-Cadherin, a cell adhesion protein, has been shown to take part in the compartmentalization, proliferation, survival, and differentiation of cells. E-Cadherin is expressed in the adult and embryonic forebrain germinal zones in vivo, and in clonal colonies of cells derived from these regions and grown in vitro. Mice carrying E-Cadherin floxed genes crossed to mice expressing Cre under the Nestin promoter demonstrate defects in the self-renewal of neural stem cells both in vivo and in vitro. The functional role of E-Cadherin is further demonstrated using adhesion-blocking antibodies in vitro, which specifically target cadherin extracellular adhesive domains. Adult neural stem cell colonies decrease in the presence of E-Cadherin antibodies in a dosage-dependent manner, in contrast to P-Cadherin antibody. On overexpression of normal E-Cadherin and a mutated E-Cadherin, containing no intracellular binding domain, an increased number of clonal adult neural stem cell colonies are observed. These data suggest it is specifically E-Cadherin adhesion that is responsible for these self-renewal effects. These data show the importance of E-Cadherin in the neural stem cell niche and suggest E-Cadherin regulates the number of these cells

A progressive and cell non-autonomous increase in striatal neural stem cells in the Huntington's disease R6/2 mouse

Neural stem and progenitor cells are located in the subependyma of the adult forebrain. An increase in adult subependymal cell proliferation is reported after various kinds of brain injury. We demonstrate an expansion of neural precursor cells in the postnatal subependyma in a murine genetic disease model of Huntington's disease (HD), the R6/2 mouse. We used the in vitro neurosphere assay as an index of the number of neural stem cells in vivo and to assess proliferation kinetics in vitro and in vivo bromodeoxyuridine labeling to assess the progenitor cell population and their fates. Disease progression in this model leads to an increase in the numbers of neural stem cells in the adult striatal subependyma. This increase is produced cell non-autonomously by events in the R6/2 brains as the mice become increasingly symptomatic. Once the neural stem cell increase is induced in vivo, it is maintained during in vitro passaging of neural stem cells, but the neural stem cell increase is not reproduced during in vitro passaging of neural stem cells from presymptomatic R6/2 mice. In addition, we show that some of the R6/2 neural progenitor cells show a change from their normal migration destiny toward the olfactory bulb. Instead, some of these cells migrate into the striatum, one of the main affected areas in HD. Our findings demonstrate that HD damage recruits precursor cells in two ways: expansion of neural stem cells and altered migration of progenitor cells

Pathogenic KDM5B variants in the context of developmental disorders

Histone modifying enzymes are involved in the posttranslational modification of histones and the epigenetic control of gene expression. They play a critical role in normal development, and there is increasing evidence of their role in developmental disorders (DDs). DDs are a group of chronic, severe conditions that impact the physical, intellectual, language and/or behavioral development of an individual. There are very few treatment options available for DDs such that these are conditions with significant unmet clinical need. Recessive variants in the gene encoding histone modifying enzyme KDM5B are associated with a DD characterized by developmental delay, facial dysmorphism and camptodactyly. KDM5B is responsible for the demethylation of lysine 4 on the amino tail of histone 3 and plays a vital role in normal development and regulating cell differentiation. This review explores the literature on KDM5B and what is currently known about its roles in development and developmental disorders