The major goals of this proposal are to understand the molecular basis of neuronal and glial differentiation in the developing nervous system. Here, the mechanisms that control sequential motor neuron and oligodendrocyte differentiation from a single progenitor domain (pMN) within the spinal cord will be investigated. GDE2, a six-transmembrane (6-TM) protein that contains an extracellular glycerophosphodiester phosphodiesterase (GDPD) domain is necessary and sufficient to induce motor neuron differentiation through GDPD activity. In this proposal, biochemical and in vivo approaches will be used to define the mechanism of GDE2 GDPD activity and identify potential physiological substrates of 6- TM GDPD enzymatic function. Strikingly, a second 6-TM GDE protein shows complementary expression to GDE2 that is coincident with oligodendrocyte generation. In vivo and in vitro approaches will be taken to test the function of this second GDPD regulatory system in oligodendrocyte specification, differentiation and maturation. Genetic ablation of GDE2 results in increased numbers of oligodendrocytes in the gliogenic period, suggesting that GDE2 might prevent the premature initiation of oligodendrocyte differentiation. This hypothesis will be tested using a combination of biochemical, genetic and functional approaches. Taken together, these studies will provide mechanistic insight into novel GDPD-dependent regulatory systems that control motor neuron and oligodendrocyte differentiation, and determine if they intersect to regulate the temporal control of neurogenesis and gliogenesis in the spinal cord.

Public Health Relevance

The studies proposed will define the mechanism, function and intersection of novel GDPD driven pathways in regulating neurogenesis and oligodendrogenesis in the developing nervous system. The outcomes from this work will significantly advance current understanding of the control of cellular signaling and will be directly relevant to basic ad translational approaches to ameliorate or cure diseases affecting nervous system function.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Gubitz, Amelie
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Johns Hopkins University
Schools of Medicine
United States
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Cave, Clinton; Sockanathan, Shanthini (2018) Transcription factor mechanisms guiding motor neuron differentiation and diversification. Curr Opin Neurobiol 53:1-7
Cave, Clinton; Park, Sungjin; Rodriguez, Marianeli et al. (2017) GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord. Mol Neurodegener 12:8
Hatori, Yuta; Yan, Ye; Schmidt, Katharina et al. (2016) Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway. Nat Commun 7:10640
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Park, Sungjin; Lee, Changhee; Sabharwal, Priyanka et al. (2013) GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science 339:324-8
Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin et al. (2011) GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling. Neuron 71:1058-70
Periz, Goran; Yan, Ye; Bitzer, Zachary T et al. (2010) GDP-bound Galphai2 regulates spinal motor neuron differentiation through interaction with GDE2. Dev Biol 341:213-21
Ji, Sheng-Jian; Periz, Goran; Sockanathan, Shanthini (2009) Nolz1 is induced by retinoid signals and controls motoneuron subtype identity through distinct repressor activities. Development 136:231-40
Yan, Ye; Sabharwal, Priyanka; Rao, Meenakshi et al. (2009) The antioxidant enzyme Prdx1 controls neuronal differentiation by thiol-redox-dependent activation of GDE2. Cell 138:1209-21
Zhuang, BinQuan; Su, YouRong Sophie; Sockanathan, Shanthini (2009) FARP1 promotes the dendritic growth of spinal motor neuron subtypes through transmembrane Semaphorin6A and PlexinA4 signaling. Neuron 61:359-72

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