Jean-Ju Chung, PhD

Assistant Professor of Cellular & Molecular Physiology

Research Interests

Fertility; Ion Channels; Reproduction; Sperm Capacitation; Sperm Motility; Signal Transduction; Membrane Microdomains

Research Organizations

Cellular & Molecular Physiology

Yale Combined Program in the Biological and Biomedical Sciences (BBS): Molecular Medicine, Pharmacology, and Physiology: Cytoskeleton and Cell Migration/Morphogenesis; Genetics, Genomics and Proteomics; Ion Channels, Pumps and Transporters; Protein Sorting and Trafficking; Receptors and Signal Transduction

Faculty Research

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.

Selected Publications

Full List of PubMed Publications

Edit this profile

Contact Info

Jean-Ju Chung, PhD
Lab Location
E07Sterling Hall of Medicine, B-Wing
333 Cedar Street

New Haven, CT 06510
View on map...
Office Location
E36CSterling Hall of Medicine, B-Wing
333 Cedar Street

New Haven, CT 06510
View on map...
Mailing Address
Yale School of Medicine, SHM-B147
333 Cedar street

New Haven, CT 06510

Curriculum Vitae

Ion Channels & Reproductive Physiology Lab @ Yale

An Exotic Cell with the Sac to Spill

Mammalian sperm, a highly specialized cell, has a well defined cap (acrosome) that covers of the sperm head and elaborate cytoskeletal structures in the tail. Shown here is an x-y projection of three dimensional structured illumination microscopy (3D-SIM) image of a sperm head with the connecting sperm tail from transgenic mice expressing EGFP in the head (green) and DsRed in mitochondrial sheath (red). Lectins (cyan) are used to probe the unique distribution of glycoproteins over the acrosome edge in the head and the flagella membrane.

Linear Ca2+ Signaling Domains in Flagella

Precisely localized, scaffolded Ca2+ channel complexes are essential for proper Ca2+ signaling. In the sperm principal piece, which lacks ER and mitochondria, highly organized Ca2+ channels and signaling molecules in the plasma membrane are responsible for localizing Ca2+ signals (Chung et al, 2014, Cell 157:808-822). The sperm-specific calcium channel, CatSper, transduces Ca2+ signals that mediate hyperactivated motility in the mouse spermatozoa. Three dimensional-photoactivated localization microscopy (3D-PALM) reveals that CatSper channels are organized in four linear domains along the flagellum. Shown here is an x-y projection of two sperm tails, with each color representing the relative distance from the focal plane along the z-axis. This compartmentalized organization may help tune the Ca2+ signaling, thus enable faster engagement of effectors. Because sperm rotate about their longitudinal axis as they rheotax (Miki and Clapham, 2013, Curr. Biol. 23: 443-452), the multilinear arrangement of CatSper may conserve space and enhance detection of finite signals.