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      Neurotrophic Factor-α1: A Key Wnt-β-Catenin Dependent Anti-Proliferation Factor and ERK-Sox9 Activated Inducer of Embryonic Neural Stem Cell Differentiation to Astrocytes in Neurodevelopment : NF-α1 in Stem Cell Differentiation

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          Abstract

          Embryonic neurodevelopment involves inhibition of proliferation of multipotent neural stem cells (NSCs) followed by differentiation into neurons, astrocytes and oligodendrocytes to form the brain. We have identified a new neurotrophic factor, NF-α1, which inhibits proliferation and promotes differentiation of NSC/progenitors derived from E13.5 mouse cortex. Inhibition of proliferation of these cells was mediated through negatively regulating the Wnt pathway and decreasing β-catenin. NF-α1 induced differentiation of NSCs to astrocytes by enhancing Glial Fibrillary Acidic Protein (GFAP) expression through activating the ERK1/2-Sox9 signaling pathway. Cultured E13.5 cortical stem cells from NF-α1-knockout mice showed decreased astrocyte numbers compared to wild-type mice, which was rescued by treatment with NF-α1. In vivo, immunocytochemistry of brain sections and Western blot analysis of neocortex of mice showed a gradual increase of NF-α1 expression from E14.5 to P1 and a surge of GFAP expression at P1, the time of increase in astrogenesis. Importantly, NF-α1-Knockout mice showed ∼49% fewer GFAP positive astrocytes in the neocortex compared to WT mice at P1. Thus, NF-α1 is critical for regulating antiproliferation and cell fate determination, through differentiating embryonic stem cells to GFAP-positive astrocytes for normal neurodevelopment. Stem Cells 2017;35:557-571.

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          Astrocytes Control Synapse Formation, Function, and Elimination.

          Astrocytes, through their close associations with synapses, can monitor and alter synaptic function, thus actively controlling synaptic transmission in the adult brain. Besides their important role at adult synapses, in the last three decades a number of critical findings have highlighted the importance of astrocytes in the establishment of synaptic connectivity in the developing brain. In this article, we will review the key findings on astrocytic control of synapse formation, function, and elimination. First, we will summarize our current structural and functional understanding of astrocytes at the synapse. Then, we will discuss the cellular and molecular mechanisms through which developing and mature astrocytes instruct the formation, maturation, and refinement of synapses. Our aim is to provide an overview of astrocytes as important players in the establishment of a functional nervous system.
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            Astrocytes and disease: a neurodevelopmental perspective.

            Astrocytes are no longer seen as a homogenous population of cells. In fact, recent studies indicate that astrocytes are morphologically and functionally diverse and play critical roles in neurodevelopmental diseases such as Rett syndrome and fragile X mental retardation. This review summarizes recent advances in astrocyte development, including the role of neural tube patterning in specification and developmental functions of astrocytes during synaptogenesis. We propose here that a precise understanding of astrocyte development is critical to defining heterogeneity and could lead advances in understanding and treating a variety of neuropsychiatric diseases.
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              Distribution of pre-pro-glucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system.

              Glucagon-like peptide-1 (GLP-1) is derived from the peptide precursor pre-pro-glucagon (PPG) by enzymatic cleavage and acts via its receptor, glucagon-like peptide-1 receptor (GLP-1R). By using riboprobes complementary to PPG and GLP-1R, we described the distribution of PPG and GLP-1R messenger RNAs (mRNAs) in the central nervous system of the rat. PPG mRNA-expressing perikarya were restricted to the nucleus of the solitary tact or to the dorsal and ventral medulla and olfactory bulb. GLP-1R mRNA was detected in numerous brain regions, including the mitral cell layer of the olfactory bulb; temporal cortex; caudal hippocampus; lateral septum; amygdala; nucleus accumbens; ventral pallium; nucleus basalis Meynert; bed nucleus of the stria terminalis; preoptic area; paraventricular, supraoptic, arcuate, and dorsomedial nuclei of the hypothalamus; lateral habenula; zona incerta; substantia innominata; posterior thalamic nuclei; ventral tegmental area; dorsal tegmental, posterodorsal tegmental, and interpeduncular nuclei; substantia nigra, central gray; raphe nuclei; parabrachial nuclei; locus ceruleus, nucleus of the solitary tract; area postrema; dorsal nucleus of the vagus; lateral reticular nucleus; and spinal cord. These studies, in addition to describing the sites of GLP-1 and GLP-1R synthesis, suggest that the efferent connections from the nucleus of the solitary tract are more widespread than previously reported. Although the current role of GLP-1 in regulating neuronal physiology is not known, these studies provide detailed information about the sites of GLP-1 synthesis and potential sites of action, an important first step in evaluating the function of GLP-1 in the brain. The widespread distribution of GLP-1R mRNA-containing cells strongly suggests that GLP-1 not only functions as a satiety factor but also acts as a neurotransmitter or neuromodulator in anatomically and functionally distinct areas of the central nervous system.
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                Author and article information

                Journal
                STEM CELLS
                Stem Cells
                Wiley
                10665099
                March 2017
                March 2017
                October 26 2016
                : 35
                : 3
                : 557-571
                Affiliations
                [1 ]Section on Cellular Neurobiology; Bethesda Maryland USA
                [2 ]Unit on Developmental Neurogenetics; Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Bethesda Maryland USA
                [3 ]Department of Epidemiology and Public Health and Anatomy and Neurobiology; University of Maryland; Baltimore Maryland USA
                Article
                10.1002/stem.2511
                6131007
                27709799
                64ebdde1-b9c6-4c10-9f38-b73b71851877
                © 2016

                http://doi.wiley.com/10.1002/tdm_license_1.1

                http://onlinelibrary.wiley.com/termsAndConditions#vor

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