Jean-Ju Chung, PhD
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Research Summary
Life perpetuates through successful fertilization. We study membrane receptors, ion channels, and their downstream signaling molecules that regulate sperm motility and fertility in mammals. In particular, we study the primary calcium channel “CatSper” and its accessory subunits. Strong evolutionary pressure on reproduction have endowed sperm with highly evolved and specialized calcium signaling complexes. A long-term goal is to elucidate the unique molecular and structural adaptations in the ion channels complex that mediate successful fertilization as well as other critical, physiological events in mammalian reproduction. To this end, we use a variety of approaches including mouse genetics, biochemical studies, dynamic optical imaging of live cells, and cutting-edge super-resolution microscopy. Our research has clinical implications in the treatment of human infertility as well as contraception, and expands our understanding of calcium signaling.
Extensive Research Description
In humans, only about 200 out of 200 million spermatozoa ever reach the oviduct and of these only one spermatozoon fertilizes the egg. During the life-changing journey, sperm cells not only adapt to changes in local environments, but also respond to cues along the female reproductive tract. Ion channels and transporters enable sperm to respond to the constantly changing environment by controlling the sperm’s calcium and proton concentrations that in turn results in changes in motility. However, the molecular details are largely unknown.
A current focus of our research is to understand the mechanisms by which the sperm motility and male fertility are regulated by ion channels. In particular, we are studying the sperm-specific calcium channels “CatSpers” that are essential for sperm hyperactivation (an asymmetric flagellar motion of the sperm tail that gives spermatozoa the force to penetrate the zona pellucida of the egg.)
First, we characterized the native CatSper channel complex, identifying novel CatSper accessory subunits to better understand molecular organization of the CatSper channel and its signal transduction in mammalian fertilization. The accessory subunits are key to understand the assembly and the organization of an ion channel complex. By generating mice lacking each subunit we found that one of their function is to protect the pore-forming subunits from premature degradation, and that only the properly assembled, complete channel complex can be specifically targeted to the flagellar membrane.
Calcium signaling specificity is accomplished via the ion’s precise spatiotemporal localization in a cell. Mammalian sperm has elaborate cytoskeletal structures in the tail for motility regulation. As the sperm flagella is less than 1 um in diameter, the spatial information of the signaling molecules inside the flagella cannot be resolved by conventional light microscope due to diffraction limit of light. Thus, we have applied super-resolution stochastic optical reconstruction microscopy (STORM) to image CatSper and the potential downstream signaling molecules within the flagella. Our studies showed that the CatSper channel forms unique four linear calcium domains that organize calcium signaling proteins along the flagella, providing strong evidence for molecularly defined, structured calcium signaling domains. These domains orchestrate the timing and extent of complex phosphorylation cascade, potentially coordinating the flagellar waveform. We are currently studying the molecular mechanisms by which CatSper and calcium signaling molecules are organized in the four distinct lines.
Most importantly, we demonstrated that capacitation (a physiological process that enables spermatozoa to obtain the fertilizing ability in the female reproductive system through biochemical and functional changes) results in heterogeneous sperm populations with molecular differences in the CatSper spatial domains. These data suggest that the exceptionally few spermatozoa that reach the egg have a distinct molecular signature from those that fail in the female reproductive tract! Ongoing projects address characterization of the successful spermatozoa at the molecular levels. We are particularly interested in the molecular changes of the sperm membrane receptors and ion channels during navigation in the female reproductive tracts in situ.
Disruption of many of membrane receptors and ion channels leads to infertility in humans. The information gained from our research will improve in vitro fertilization methods and enable new contraceptive approaches. Ultimately, our research shall explain they very first life event that allows all the subsequent animal physiology.
Coauthors
Research Interests
Fertility; Ion Channels; Reproduction; Sperm Capacitation; Sperm Motility; Signal Transduction; Membrane Microdomains
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Selected Publications
- CatSper Calcium Channels: 20 Years OnHwang J, Chung J. CatSper Calcium Channels: 20 Years On Physiology 2022, 38: 125-140. PMID: 36512352, PMCID: PMC10085559, DOI: 10.1152/physiol.00028.2022.
- Selenoprotein TXNRD3 supports male fertility via the redox regulation of spermatogenesisDou Q, Turanov AA, Mariotti M, Hwang JY, Wang H, Lee SG, Paulo JA, Yim SH, Gygi SP, Chung JJ, Gladyshev VN. Selenoprotein TXNRD3 supports male fertility via the redox regulation of spermatogenesis Journal Of Biological Chemistry 2022, 298: 102183. PMID: 35753352, PMCID: PMC9352919, DOI: 10.1016/j.jbc.2022.102183.
- 3D structure and in situ arrangements of CatSper channel in the sperm flagellumZhao Y, Wang H, Wiesehoefer C, Shah NB, Reetz E, Hwang JY, Huang X, Wang TE, Lishko PV, Davies KM, Wennemuth G, Nicastro D, Chung JJ. 3D structure and in situ arrangements of CatSper channel in the sperm flagellum Nature Communications 2022, 13: 3439. PMID: 35715406, PMCID: PMC9205950, DOI: 10.1038/s41467-022-31050-8.
- Redox regulation by TXNRD3 during epididymal maturation underlies capacitation-associated mitochondrial activity and sperm motility in miceWang H, Dou Q, Jeong KJ, Choi J, Gladyshev VN, Chung JJ. Redox regulation by TXNRD3 during epididymal maturation underlies capacitation-associated mitochondrial activity and sperm motility in mice Journal Of Biological Chemistry 2022, 298: 102077. PMID: 35643315, PMCID: PMC9218152, DOI: 10.1016/j.jbc.2022.102077.
- CatSper and its CaM‐like Ca2+ sensor EFCAB9 are necessary for the path chirality of spermWiesehöfer C, Wiesehöfer M, Dankert JT, Chung J, Ostau N, Singer BB, Wennemuth G. CatSper and its CaM‐like Ca2+ sensor EFCAB9 are necessary for the path chirality of sperm The FASEB Journal 2022, 36: e22288. PMID: 35438819, PMCID: PMC9835897, DOI: 10.1096/fj.202101656rr.
- CatSper and Two-Pore channels (TPC) in GtoPdb v.2022.1Chung J, Clapham D, Garbers D, Grimm C, Ren D. CatSper and Two-Pore channels (TPC) in GtoPdb v.2022.1 IUPHAR/BPS Guide To Pharmacology CITE 2022, 2022 DOI: 10.2218/gtopdb/f70/2022.1.
- C2cd6-encoded CatSperτ targets sperm calcium channel to Ca2+ signaling domains in the flagellar membraneHwang JY, Wang H, Lu Y, Ikawa M, Chung JJ. C2cd6-encoded CatSperτ targets sperm calcium channel to Ca2+ signaling domains in the flagellar membrane Cell Reports 2022, 38: 110226. PMID: 34998468, PMCID: PMC8857959, DOI: 10.1016/j.celrep.2021.110226.
- Mitochondria–cytoskeleton interactions in mammalian sperm revealed by cryoelectron tomographyWang H, Chung JJ. Mitochondria–cytoskeleton interactions in mammalian sperm revealed by cryoelectron tomography Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2118020118. PMID: 34819381, PMCID: PMC8640839, DOI: 10.1073/pnas.2118020118.
- Molecular Evolution of CatSper in Mammals and Function of Sperm Hyperactivation in Gray Short-Tailed OpossumHwang JY, Maziarz J, Wagner GP, Chung JJ. Molecular Evolution of CatSper in Mammals and Function of Sperm Hyperactivation in Gray Short-Tailed Opossum Cells 2021, 10: 1047. PMID: 33946695, PMCID: PMC8147001, DOI: 10.3390/cells10051047.
- Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and MiceHwang JY, Nawaz S, Choi J, Wang H, Hussain S, Nawaz M, Lopez-Giraldez F, Jeong K, Dong W, Oh JN, Bilguvar K, Mane S, Lee CK, Bystroff C, Lifton RP, Ahmad W, Chung JJ. Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice Frontiers In Cell And Developmental Biology 2021, 9: 662903. PMID: 33968937, PMCID: PMC8103034, DOI: 10.3389/fcell.2021.662903.
- Sperm ion channels and transporters in male fertility and infertilityWang H, McGoldrick LL, Chung JJ. Sperm ion channels and transporters in male fertility and infertility Nature Reviews Urology 2020, 18: 46-66. PMID: 33214707, PMCID: PMC7852504, DOI: 10.1038/s41585-020-00390-9.
- 3D in situ imaging of female reproductive tract reveals molecular signatures of fertilizing spermatozoa in miceDed L, Hwang JY, Miki K, Shi HF, Chung JJ. 3D in situ imaging of female reproductive tract reveals molecular signatures of fertilizing spermatozoa in mice ELife 2020, 9: e62043. PMID: 33078708, PMCID: PMC7707823, DOI: 10.7554/elife.62043.
- CatSper and Two-Pore channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology DatabaseChung J, Clapham D, Garbers D, Ren D. CatSper and Two-Pore channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database IUPHAR/BPS Guide To Pharmacology CITE 2019, 2019 DOI: 10.2218/gtopdb/f70/2019.4.
- Dual Sensing of Physiologic pH and Calcium by EFCAB9 Regulates Sperm MotilityHwang JY, Mannowetz N, Zhang Y, Everley RA, Gygi SP, Bewersdorf J, Lishko PV, Chung JJ. Dual Sensing of Physiologic pH and Calcium by EFCAB9 Regulates Sperm Motility Cell 2019, 177: 1480-1494.e19. PMID: 31056283, PMCID: PMC8808721, DOI: 10.1016/j.cell.2019.03.047.
- CatSperζ regulates the structural continuity of sperm Ca2+ signaling domains and is required for normal fertilityChung JJ, Miki K, Kim D, Shim SH, Shi HF, Hwang JY, Cai X, Iseri Y, Zhuang X, Clapham DE. CatSperζ regulates the structural continuity of sperm Ca2+ signaling domains and is required for normal fertility ELife 2017, 6: e23082. PMID: 28226241, PMCID: PMC5362262, DOI: 10.7554/elife.23082.
- Sugar‐coated spermChung J. Sugar‐coated sperm Molecular Reproduction And Development 2016, 83: 859-859. PMID: 27591546, DOI: 10.1002/mrd.22732.
- Sperm flagellar Ca2+ signaling domainsChung J. Sperm flagellar Ca2+ signaling domains Molecular Reproduction And Development 2016, 83: 275-275. DOI: 10.1002/mrd.22628.
- Structurally Distinct Ca2+ Signaling Domains of Sperm Flagella Orchestrate Tyrosine Phosphorylation and MotilityChung JJ, Shim SH, Everley RA, Gygi SP, Zhuang X, Clapham DE. Structurally Distinct Ca2+ Signaling Domains of Sperm Flagella Orchestrate Tyrosine Phosphorylation and Motility Cell 2014, 157: 808-822. PMID: 24813608, PMCID: PMC4032590, DOI: 10.1016/j.cell.2014.02.056.
- Structurally Distinct Ca2+ Domains of Sperm Flagella Modulate Hyperactivated MotilityShim S, Chung J, Zhuang X, Clapham D. Structurally Distinct Ca2+ Domains of Sperm Flagella Modulate Hyperactivated Motility Biophysical Journal 2014, 106: 436a. DOI: 10.1016/j.bpj.2013.11.2454.
- Catsper Channel Organizes and Regulates Calcium Signaling Molecules in SpermatozoaChung J, Shim S, Zhuang X, Clapham D. Catsper Channel Organizes and Regulates Calcium Signaling Molecules in Spermatozoa Biophysical Journal 2013, 104: 633a. DOI: 10.1016/j.bpj.2012.11.3501.
- A novel Gene Required for Male Fertility and Functional Catsper Channel Formation in SpermatozoaChung J, Navarro B, Krapivinsky G, Krapivinsky L, Clapham D. A novel Gene Required for Male Fertility and Functional Catsper Channel Formation in Spermatozoa Biophysical Journal 2011, 100: 90a. DOI: 10.1016/j.bpj.2010.12.698.
- A novel gene required for male fertility and functional CATSPER channel formation in spermatozoaChung JJ, Navarro B, Krapivinsky G, Krapivinsky L, Clapham DE. A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa Nature Communications 2011, 2: 153. PMID: 21224844, PMCID: PMC3999383, DOI: 10.1038/ncomms1153.
- PI3K/Akt signalling‐mediated protein surface expression sensed by 14‐3‐3 interacting motifChung J, Okamoto Y, Coblitz B, Li M, Qiu Y, Shikano S. PI3K/Akt signalling‐mediated protein surface expression sensed by 14‐3‐3 interacting motif The FEBS Journal 2009, 276: 5547-5558. PMID: 19691494, PMCID: PMC4301307, DOI: 10.1111/j.1742-4658.2009.07241.x.
- Ion channels that control fertility in mammalian spermatozoaNavarro B, Kirichok Y, Chung JJ, Clapham DE. Ion channels that control fertility in mammalian spermatozoa The International Journal Of Developmental Biology 2008, 52: 607-613. PMID: 18649274, PMCID: PMC4297656, DOI: 10.1387/ijdb.072554bn.
- Biochemical characterization of the native Kv2.1 potassium channelChung J, Li M. Biochemical characterization of the native Kv2.1 potassium channel The FEBS Journal 2005, 272: 3743-3755. PMID: 16008572, DOI: 10.1111/j.1742-4658.2005.04802.x.
- Genome-wide Analyses of Carboxyl-terminal Sequences*Chung JJ, Yang H, Li M. Genome-wide Analyses of Carboxyl-terminal Sequences* Molecular & Cellular Proteomics 2003, 2: 173-181. PMID: 12682279, DOI: 10.1074/mcp.m300008-mcp200.
- Functional diversity of protein C-termini: more than zipcoding?Chung J, Shikano S, Hanyu Y, Li M. Functional diversity of protein C-termini: more than zipcoding? Trends In Cell Biology 2002, 12: 146-150. PMID: 11859027, DOI: 10.1016/s0962-8924(01)02241-3.
- 9-cis-Retinoic acid represses transcription of the gonadotropin-releasing hormone (GnRH) gene via proximal promoter region that is distinct from all-trans-retinoic acid response elementCho S, Chung J, Han J, Lee B, Do Han Kim, Rhee K, Kim K. 9-cis-Retinoic acid represses transcription of the gonadotropin-releasing hormone (GnRH) gene via proximal promoter region that is distinct from all-trans-retinoic acid response element Brain Research 2001, 87: 214-222. PMID: 11245924, DOI: 10.1016/s0169-328x(01)00020-1.
- A functional retinoic acid response element (RARE) is present within the distal promoter of the rat gonadotropin-releasing hormone (GnRH) geneCho S, Chung J, Choe Y, Choi H, Do Han Kim, Rhee K, Kim K. A functional retinoic acid response element (RARE) is present within the distal promoter of the rat gonadotropin-releasing hormone (GnRH) gene Brain Research 2001, 87: 204-213. PMID: 11245923, DOI: 10.1016/s0169-328x(01)00021-3.
- Activation of retinoic acid receptor γ induces proliferation of immortalized hippocampal progenitor cellsChung J, Cho S, Kwon Y, Do Han Kim, Kim K. Activation of retinoic acid receptor γ induces proliferation of immortalized hippocampal progenitor cells Brain Research 2000, 83: 52-62. PMID: 11072095, DOI: 10.1016/s0169-328x(00)00196-0.
- Functional impairment of lens aquaporin in two families with dominantly inherited cataractsFrancis P, Chung JJ, Yasui M, Berry V, Moore A, Wyatt MK, Wistow G, Bhattacharya SS, Agre P. Functional impairment of lens aquaporin in two families with dominantly inherited cataracts Human Molecular Genetics 2000, 9: 2329-2334. PMID: 11001937, DOI: 10.1093/oxfordjournals.hmg.a018925.