The human nervous system consists of thousands of cell types with distinct patterns of gene expression and functions. One general way to diversify neuronal subtypes is to specify different identities and functions of individual cell types through stochastic neuronal fate choices. However, the mechanisms that generate stochastic cellular diversity in the nervous system are only partly understood. The C. elegans left and right AWC olfactory neurons specify asymmetric subtypes through a stochastic, coordinated cell signaling event, which allows the animal to discriminate between different odors. We have identified that this stochastic cell fate choice is regulated through a transient, embryonic NSY-5/innexin gap junction neural network that antagonizes a downstream Ca2+-regulated pathway to establish long-lasting asymmetric AWC identities. The overall goal of this proposal is to use this system as a model to identify the molecular mechanisms by which gap junction-mediated transient signaling events coordinate long- term stochastic neuronal fate choice. In this grant proposal, we will test the hypothesis that intercellular Ca2+ signaling mediates communication between AWCs and non-AWCs in the nsy-5 neural network to coordinate stochastic AWC subtype choice (Aim 1), investigate the role of Ca2+-activated SLO K+ channels and newly identified MOK (modifier of K+ channel) molecules in AWC subtype choice (Aim 2), and identify the mechanisms that regulate the synaptic localization of the TIR-1/Sarm1 Ca2+ signaling scaffold protein for AWC subtype choice (Aim 3). The establishment of long-lasting neuronal subtypes by a transient gap junction-dependent cell network provides an innovative, robust, and simple system to elucidate the molecular mechanisms underlying the biological function of gap junction-mediated intercellular signaling in development in vivo, which is not readily feasible in vertebrates. As mutations in the human homologs of the genes we study are associated with a variety of developmental disorders, understanding normal functions of these genes in mechanistic detail will inform novel therapeutic strategies.

Public Health Relevance

Developmental disorders asociated with defects in neuronal development cause enormous human suffering. Since stochastic cell fate acquisition and gap junction- mediated signaling are two conserved and central problems in neural development, understanding mechanisms of stochastic cellular diversity and gap junction function in the nervous system may elucidate the disease processes resulting from early defects in these events and provide models for their eventual repair. The proteins (gap junctions, voltage-activated Ca2+ chanels, Ca2+-activated K+ chanels, and the TIR-1/Sarm1 scaffold protein) we study are conserved and widely distributed in the vertebrate nervous system and many other organs, and mutations in the human homologs of these genes are associated with a variety of developmental disorders such as peripheral neuropathy, autism, and epilepsy. Thus, a better understanding of normal functions of these genes in mechanistic detail will inform novel therapeutic strategies.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Neurogenesis and Cell Fate Study Section (NCF)
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Hoodbhoy, Tanya
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Cincinnati Children's Hospital Medical Center
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Chiu, Hui; Zou, Yan; Suzuki, Nobuko et al. (2018) Engulfing cells promote neuronal regeneration and remove neuronal debris through distinct biochemical functions of CED-1. Nat Commun 9:4842
Alqadah, Amel; Hsieh, Yi-Wen; Morrissey, Zachery D et al. (2018) Asymmetric development of the nervous system. Dev Dyn 247:124-137
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Hsieh, Yi-Wen; Alqadah, Amel; Chuang, Chiou-Fen (2016) An Optimized Protocol for Electrophoretic Mobility Shift Assay Using Infrared Fluorescent Dye-labeled Oligonucleotides. J Vis Exp :
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Alqadah, Amel; Hsieh, Yi-Wen; Chuang, Chiou-Fen (2016) Sox2 goes beyond stem cell biology. Cell Cycle 15:777-8
Alqadah, Amel; Hsieh, Yi-Wen; Vidal, Berta et al. (2015) Postmitotic diversification of olfactory neuron types is mediated by differential activities of the HMG-box transcription factor SOX-2. EMBO J 34:2574-89
Vidal, Berta; Santella, Anthony; Serrano-Saiz, Esther et al. (2015) C. elegans SoxB genes are dispensable for embryonic neurogenesis but required for terminal differentiation of specific neuron types. Development 142:2464-77
Alqadah, Amel; Hsieh, Yi-Wen; Chuang, Chiou-Fen (2014) A molecular link between distinct neuronal asymmetries. Cell Cycle 13:1515-6

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