Associate Professor of Neurobiology
Cell Signaling, Neuron-Glial Interaction, GPI-anchored Proteins, Extracellular Matrix Organization
Cell-to-cell and cell-to-extracellular matrix (ECM) communication is critical for development and function of the nervous system. We study signaling pathways mediated by glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-APs). GPI-APs play key roles in multiple processes including neurogenesis, axon guidance, synapse development and ECM formation. GPI-APs are a unique hybrid class of proteins that are both membrane bound, as well as cleaved and released from the membrane and thus play versatile roles in signal transduction on the cell surface and in the extracellular space. However, how GPI-dependent signaling pathways are regulated is poorly understood. By focusing on understudied pathways we hope to identify novel therapeutic targets for neurodevelopmental diseases caused by synaptogenic defects such as autism spectrum disorders and schizophrenia.
Mechanisms of Bi-Directional Neuron-Astrocyte Communication Regulating Synapse Development and Function
Astrocytes play important roles in multiple steps of synapse formation and function, many of which are mediated by released factors. However, the mechanism of release of these factors remains elusive. We have identified a novel pathway to release GPI-anchored synaptogenic factors from astrocytes via an astrocyte-specific GPI-anchor cleaving enzyme. We are investigating its regulatory mechanism and specific downstream effectors.
Is the release of synaptogenic factors constitutive or regulated by neuronal activity? We are working to identify specific signaling molecules secreted from neurons that facilitate the release of synaptogenic factors from astrocytes. Specifically, we are studying the regulated release of glypican-4, a GPI-anchored protein and how the GPI-anchor itself may play a role in this mechanism. We have generated a knock-in mouse line to study the contribution of the released vs membrane-bound forms of glypican-4 signaling both in vitro and in vivo.
Molecular Mechanisms Mediating the Formation of Highly Ordered ECM Structures
How are complex ECM structures established outside the cell? What molecular mechanisms drive the assembly of the ECM? We focus on a specialized ECM structure in the inner ear, the tectorial membrane, which plays roles in amplification and propagation of sound waves. We found that GPI-anchorage of alpha-tectorin is required to prevent diffusion of ECM components and allow assembly of the tectorial membrane. We are currently investigating how its growth and characteristic ultrastructure are specified at the molecular level using newly generated knock-in mouse lines.
Development and Applications of a High-Throughput Live neuronal Activity Assay
Can we perform high-thought drug screen assay to identify drugs that modulate synapse development and function? Can we generate mutant neurons that bear a disease-causing mutation and simultaneously monitor altered neuronal activity only in the mutated neurons? We have developed a simple and robust assay to monitor the neuronal activity in live neurons by combining activity-dependent promoters and secreted reporters. We are optimizing this assay to establish large-scale analyses, drug screens and to combine it with cutting edge gene-editing techniques in order to study the effects of disease-causing mutations.
- Huang K, Park S. Heparan Sulfated Glypican-4 Is Released from Astrocytes by Proteolytic Shedding and GPI-Anchor Cleavage Mechanisms. eNeuro. 2021 Jul-Aug;8(4). doi: 10.1523/ENEURO.0069-21.2021. Print 2021 Jul-Aug. PubMed PMID: 34301723; PubMed Central PMCID: PMC8387153.
- Dobrowolski M, Cave C, Levy-Myers R, Lee C, Park S, Choi BR, Xiao B, Yang W, Sockanathan S. GDE3 regulates oligodendrocyte precursor proliferation via release of soluble CNTFRα. Development. 2020 Jan 23;147(2). doi: 10.1242/dev.180695. PubMed PMID: 31932351; PubMed Central PMCID: PMC6983723.
- Kim DK, Kim JA, Park J, Niazi A, Almishaal A, Park S. The release of surface-anchored α-tectorin, an apical extracellular matrix protein, mediates tectorial membrane organization. Sci Adv. 2019 Nov;5(11):eaay6300. doi: 10.1126/sciadv.aay6300. PubMed PMID: 31807709; PubMed Central PMCID: PMC6881170.
- Kim BJ, Kim DK, Han JH, Oh J, Kim AR, Lee C, Kim NK, Park HR, Kim MY, Lee S, Lee S, Oh DY, Park WY, Park S, Choi BY. Clarification of glycosylphosphatidylinositol anchorage of OTOANCORIN and human OTOA variants associated with deafness. Hum Mutat. 2019 May;40(5):525-531. doi: 10.1002/humu.23719 PubMed PMID: 30740825; PubMed Central PMCID: PMC6467692.
- Cave C, Park S, Rodriguez M, Nakamura M, Hoke A, Pletnikov M, Sockanathan S. GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord. Mol Neurodegener. 2017 Jan 19;12(1):8. doi: 10.1186/s13024-017-0148-1. PubMed PMID: 28103900; PubMed Central PMCID: PMC5244531.
- Na Y, Park S, Lee C, Kim DK, Park JM, Sockanathan S, Huganir RL, Worley PF. Real-Time Imaging Reveals Properties of Glutamate-Induced Arc/Arg 3.1 Translation in Neuronal Dendrites. Neuron. 2016 Aug 3;91(3):561-73. doi: 10.1016/j.neuron.2016.06.017. PubMed PMID: 27397520; PubMed Central PMCID: PMC5580817.
- Choi J, Park S, Sockanathan S. Activated retinoid receptors are required for the migration and fate maintenance of subsets of cortical neurons. Development. 2014 Mar;141(5):1151-60. doi: 10.1242/dev.104505 PubMed PMID: 24504337.
- Park JM, Hu JH, Milshteyn A, Zhang PW, Moore CG, Park S, Datko MC, Domingo RD, Reyes CM, Wang XJ, Etzkorn FA, Xiao B, Szumlinski KK, Kern D, Linden DJ, Worley PF. A prolyl-isomerase mediates dopamine-dependent plasticity and cocaine motor sensitization. Cell. 2013 Aug 1;154(3):637-50. doi: 10.1016/j.cell.2013.07.001. PubMed PMID: 23911326; PubMed Central PMCID: PMC3785238.
- Kim YS, Kang E, Makino Y, Park S, Shin JH, Song H, Launay P, Linden DJ. Characterizing the conductance underlying depolarization-induced slow current in cerebellar Purkinje cells. J Neurophysiol. 2013 Feb;109(4):1174-81. doi: 10.1152/jn.01168.2011. PubMed PMID: 23197456; PubMed Central PMCID: PMC3569132.
- Park S, Lee C, Sabharwal P, Zhang M, Meyers CL, Sockanathan S. GDE2 promotes neurogenesis by glycosylphosphatidylinositol-anchor cleavage of RECK. Science. 2013 Jan 18;339(6117):324-8. doi: 10.1126/science.1231921. PubMed PMID: 23329048; PubMed Central PMCID: PMC3644959.
- Rodriguez M, Choi J, Park S, Sockanathan S. Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation. Development. 2012 Oct;139(20):3870-9. doi: 10.1242/dev.081083. PubMed PMID: 22951639.
- Sabharwal P, Lee C, Park S, Rao M, Sockanathan S. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling. Neuron. 2011 Sep 22;71(6):1058-70. doi: 10.1016/j.neuron.2011.07.028. PubMed PMID: 21943603; PubMed Central PMCID: PMC3183458.
- Hu JH, Park JM, Park S, Xiao B, Dehoff MH, Kim S, Hayashi T, Schwarz MK, Huganir RL, Seeburg PH, Linden DJ, Worley PF. Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron. 2010 Dec 22;68(6):1128-42. doi: 10.1016/j.neuron.2010.11.008. PubMed PMID: 21172614; PubMed Central PMCID: PMC3013614.
- Butkinaree C, Cheung WD, Park S, Park K, Barber M, Hart GW. Characterization of beta-N-acetylglucosaminidase cleavage by caspase-3 during apoptosis. J Biol Chem. 2008 Aug 29;283(35):23557-66. doi: 10.1074/jbc.M804116200. PubMed PMID: 18586680; PubMed Central PMCID: PMC2527095.
- Park S, Park JM, Kim S, Kim JA, Shepherd JD, Smith-Hicks CL, Chowdhury S, Kaufmann W, Kuhl D, Ryazanov AG, Huganir RL, Linden DJ, Worley PF. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron. 2008 Jul 10;59(1):70-83. doi: 10.1016/j.neuron.2008.05.023. PubMed PMID: 18614030; PubMed Central PMCID: PMC2743934.
- Seong JY, Han J, Park S, Wuttke W, Jarry H, Kim K. Exonic splicing enhancer-dependent splicing of the gonadotropin-releasing hormone premessenger ribonucleic acid is mediated by tra2alpha, a 40-kilodalton serine/arginine-rich protein. Mol Endocrinol. 2002 Nov;16(11):2426-38. doi: 10.1210/me.2001-0297. PubMed PMID: 12403832.
- Seong JY, Kim BW, Park S, Son GH, Kim K. First intron excision of GnRH pre-mRNA during postnatal development of normal mice and adult hypogonadal mice. Endocrinology. 2001 Oct;142(10):4454-61. doi: 10.1210/endo.142.10.8449. PubMed PMID: 11564710.
- Park S, Seong JY, Son GH, Kang SS, Lee S, Kim SR, Kim K. Analysis of steroid-induced genes in the rat preoptic area-anterior hypothalamus using a differential-display reverse transcriptase-polymerase chain reaction. J Neuroendocrinol. 2001 Jun;13(6):531-9. doi: 10.1046/j.1365-2826.2001.00665.x. PubMed PMID: 11412340.
- Seong JY, Park S, Kim K. Enhanced splicing of the first intron from the gonadotropin-releasing hormone (GnRH) primary transcript is a prerequisite for mature GnRH messenger RNA: presence of GnRH neuron-specific splicing factors. Mol Endocrinol. 1999 Nov;13(11):1882-95. doi: 10.1210/mend.13.11.0375. PubMed PMID: 10551782.