Neurogenesis (Austin, Tex.)最新文献

Alternative splicing (AS) allows a single gene to generate multiple protein isoforms. It has been hypothesized that AS plays a role in brain wiring by increasing the number of cell recognition molecules necessary for forming connections between neurons. Many studies have characterized isoform expression patterns of various genes in the brain, but very few have addressed whether specific isoforms play a functional role in neuronal wiring. In our recent work, we reported the cell-type-specific AS of the cell recognition molecule Dscam2. Exclusive expression of Dscam2 isoforms allows tightly associated neurons to signal repulsion selectively within the same cell-types, without interfering with one another. We show that preventing cell-specific isoform expression in 2 closely associated neurons disrupts their axon terminal morphology. We propose that the requirement for isoform specificity extends to synapses and discuss experiments that can test this directly. Factors that regulate Dscam2 cell-type-specific AS likely regulate the splicing of many genes involved in neurodevelopment. These regulators of alternative splicing may act broadly to control many genes involved in the development of specific neuron types. Identifying these factors is a key step in understanding how AS contributes to the brain connectome.

Medium spiny neurons (MSNs) are the main projection neurons of the striatum and are preferentially lost in Huntington's disease (HD). With no current cure for this neurodegenerative disorder, the specificity of neuronal loss in the striatum makes cell transplantation therapy an attractive avenue for its treatment. Also, given that MSNs are particularly vulnerable in HD, it is necessary to understand why these neurons degenerate in order to develop new therapeutic options. Both approaches require access to human MSN progenitors and their mature neuronal derivatives. Human embryonic stem cells and HD patient induced pluripotent stem cells (together referred to as hPSCs) may serve as an unlimited source of such tissue if they can be directed toward authentic striatal neuronal lineage. Understanding the MSN differentiation pathway in the brain is therefore of paramount importance for the generation of accurate protocols to obtain striatal cells in vitro. The focus of this mini review will be on striatal development and current methods to generate MSNs from hPSCs.

While much progress has been made in recent years toward elucidating the transcription factor codes controlling how neural progenitor cells generate the various glial and neuronal cell types in a particular spatial domain, much less is known about how these progenitors alter their output over time. In the past years, work in the developing mouse retina has provided evidence that a transcriptional cascade similar to the one used in Drosophila neuroblasts might control progenitor temporal identity in vertebrates. The zinc finger transcription factor Ikzf1 (Ikaros), an ortholog of Drosophila hunchback, was reported to confer early temporal identity in retinal progenitors and, more recently, the ortholog of Drosophila castor, Casz1, was found to function as a mid/late temporal identity factor that is negatively regulated by Ikzf1. The molecular mechanisms by which these temporal identity factors function in retinal progenitors, however, remain unknown. Here we briefly review previous work on the vertebrate temporal identity factors in the retina, and propose a model by which they might operate.

Adeno-associated viruses (AAV) are non-pathogenic members of the Parvoviridae family that are being harnessed as delivery vehicles for both basic research and increasingly successful clinical gene therapy. To address a number of delivery shortcomings with natural AAV variants, we have developed and implemented directed evolution-a high-throughput molecular engineering approach to generate novel biomolecules with enhanced function-to create novel AAV vectors that are designed to preferentially transduce specific cell types in the central nervous system (CNS), including astrocytes, neural stem cells, and cells within the retina. These novel AAV vectors-which have enhanced infectivity in vitro and enhanced infectivity and selectivity in vivo-can enable more efficient studies to further our understanding of neurogenesis, development, aging, and disease. Furthermore, such engineered vectors may aid gene or cell replacement therapies to treat neurodegenerative disease or injury.

A population of proliferating neural stem/progenitor cells located in the subgranular zone of the adult hippocampal dentate gyrus (DG) gives rise to new neurons continuously throughout life, and this process is referred to as adult hippocampal neurogenesis. To date, it has generally been accepted that impairments of adult hippocampal neurogenesis resulting from pathological conditions such as stress, ischemia and epilepsy lead to deficits in hippocampus-dependent learning and memory tasks. Recently, we have discovered that microglia, the major immune cells in the brain, attenuate seizure-induced aberrant hippocampal neurogenesis to withstand cognitive decline and recurrent seizure. In that study, we further showed that Toll-like receptor 9, known as a pathogen-sensing receptor for innate immune system activation, recognizes self-DNA derived from degenerating neurons to induce TNF-α production in the microglia after seizure, resulting in inhibition of seizure-induced aberrant neurogenesis. Our findings provide new evidence that interaction between the innate immune and nervous systems ensures homeostatic neurogenesis in the adult hippocampus and should pave the way for the development of new therapeutic strategies for neurological diseases including epilepsy.

Temporal control of neuronal differentiation is critical to produce a complete and fully functional nervous system. Loss of the precise temporal control of neuronal cell fate can lead to defects in cognitive development and to disorders such as epilepsy and autism. Mechanistic target of rapamycin (mTOR) is a large serine/threonine kinase that acts as a crucial sensor of cellular homeostasis. mTOR signaling has recently emerged as a key regulator of neurogenesis. However, the mechanism by which mTOR regulates neurogenesis is poorly understood. In constrast to other functions of the pathway, 'neurogenic mTOR pathway factors' have not previously been identified. We have very recently used Drosophila as a model system to identify the gene unkempt as the first component of the mTOR pathway regulating neuronal differentiation. Our study demonstrates that specific adaptor proteins exist that channel mTOR signaling toward the regulation of neuronal cell fate. In this Commentary we discuss the role of mTOR signaling in neurogenesis and the significance of these findings in advancing our understanding of the mechanism by which mTOR signaling controls neuronal differentiation.