Gail Cornwall, Ph.D.
Associate Professor
e-mail: gail.cornwall@ttuhsc.edu
Biography
B.S. Zoology, 1980, Brigham Young University
M.S. Cell/Developmental Biology, 1982, Brigham Young University
Ph.D. Reproductive Biology, 1988, Johns Hopkins University School of Public Health
Postdoctoral Fellow, 1988, Vanderbilt University School of Medicine
Research Assistant Professor, 1991, Vanderbilt University School of Medicine
Assistant Professor, 1994, Texas Tech University Health Sciences Center
Associate Professor, 2001, Texas Tech University Health Sciences Center
Research Interests
Functional role of the cystatin CRES in sperm maturation and fertilization
My laboratory studies the molecular events that govern sperm maturation in the epididymis to ultimately provide new therapies for infertile couples as well as to provide potential targets for the development of male contraceptives. In particular my lab studies the CRES (cystatin-related epididymal spermatogenic) protein that defines a new reproductive-specific subgroup within the cystatin superfamily of cysteine protease inhibitors. In vitro CRES inhibits the serine protease prohormone convertase 2, an enzyme with important roles in the activation of prohormones in the neuroendocrine system. We propose that CRES, while structurally a cystatin, may have evolved to perform unique functions as mediators of substrate-specific serine proteases which may activate critical molecules important for sperm maturation and fertilization. In separate studies we are also studying the role of PC4 (prohormone convertase 4) in sperm function since mice lacking the PC4 gene are infertile possibly due to the lack of appropriate proteolytic activation of important fertilization molecules. We use mouse models including CRES and PC4 gene knockout mice in our studies.
Protein amyloidogenesis in the epididymis: mechanisms and biological significance
The abnormal accumulation of aggregated protein, also known as amyloid, is associated with degenerative diseases including Alzheimer's and Parkinson's disease. Previously disease was thought to result from the mechanical disruption of cell function due to the presence of insoluble protein aggregates. However, accumulating evidence indicates that soluble oligomeric forms of proteins, precursors to amyloid, are cytotoxic and may be the causative form. Because of the active secretion of proteins and profound removal of fluid by the epididymal epithelium, macromolecular crowding is likely to occur in the tubular lumen of the epididymis causing amyloid-type protein aggregation. Since the epididymis plays a critical role in sperm maturation, surveillance/clearance mechanisms must guard against proteins that misfold and form aggregate/amyloid structures in the lumen that could be cytotoxic to spermatozoa. Our studies demonstrate that CRES is an amyloidogenic protein and forms soluble oligomeric and ultimately Congo Red reactive fibrillar structures common to proteins associated with neurodegenerative diseases. Within the normal mouse epididymal lumen CRES also forms soluble and insoluble oligomeric complexes with no obvious associated pathologies since the mice are fertile. We hypothesize that transglutaminase, a calcium-dependent enzyme that forms stable crosslinks in proteins, may divert CRES from the amyloidogenic pathway by crosslinking it into a nontoxic amorphous structure that could ultimately be endocytosed in later epididymal regions. Thus transglutaminase may function as a mechanism of quality control for misfolded proteins in the extracellular space. Studies are currently ongoing to examine the biological significance of the CRES oligomeric structures and mechanisms, including transglutaminase, which may protect against cytotoxicities associated with amyloid structures. These studies will not only contribute to our understanding of processes integral for the maintenance of normal reproductive function but may provide novel insights of extracellular quality control mechanisms in general, possibly leading to new therapies for diseases associated with extracellular aggregated proteins such as Alzheimer's disease.
Recent Publications
von Horsten, H.H., Johnson, S.S., SanFrancisco S.K., Hastert, M.C., Whelly, S., and Cornwall, G.A. (2007). Oligomerization and transglutaminase crosslinking of the cystatin CRES in the mouse epididymal lumen: Potential mechanism of extracellular quality control. J Biol Chem, in press.[PubMed]
Cornwall, G.A., von Horsten HH, Swartz D, Johnson S, Chau K, Whelly S. (2007) Extracellular quality control in the epididymis. Asian J Androl 9:500-507.[PubMed]
Sutton-Walsh, H.G., Whelly S, and Cornwall, G.A. (2006). Differential effects of GnRH and androgens on Cres (cystatin-related epididymal spermatogenic) mRNA and protein expression in male mouse anterior pituitary gonadotroph cells. J. Andrology 27:802-815.[PubMed]
Cornwall, G.A. and von Horsten, HH. (2006) Sperm maturation in the epididymis: role of segment-specific microenvironments. In: The Genetics of Male Infertility. (Carrell, D. Ed). Humana Press.
Hsia, N., Brousal, J., Hann, S.R., and Cornwall, G.A., (2005). Recapitulation of germ cell and pituitary-specific expression with 1.6 kb of the cystatin-related epididymal spermatogenic (Cres) gene promoter in transgenic mice. J. Andrology 26:249-257. [PubMed]
Hsia N., Cornwall G.A. (2004) DNA microarray analysis of region-specific gene expression in the mouse epididymis. Biol. Reprod. 70:448-457. [PubMed] Supplemental Data (22.4 MB)
Cornwall G.A., Cameron A., Lindberg I., Hardy D.M., Cormier N., Hsia N. (2003)CRES inhibits the serine protease prohormone convertase 2. Endocrinology. 144:901-908. [PubMed]
Hsia N., Cornwall G.A. (2003)Cres2 and Cres3: new members of the CRES subgroup of family 2 cystatins. Endocrinology. 144:909-915. [PubMed]
Cornwall, G.A. and Hsia, N. (2003). A new subgroup of the family 2 cystatins. Cutting Edge Reviews: Molecular and Cellular Endocrinology. 200:1-8. [PubMed]
Wassler, M., Syntin, P., Sutton, H.G., Hsia, N., Hardy, D.M., and Cornwall, G.A. (2002). Identification and characterization of cystatin-related epididymal spermatogenic protein in human spermatozoa: localization in the equatorial segment. Biol. Reprod. 65: 1452-1461. [PubMed]
Hsia, N. and Cornwall, G.A. (2001). CCAAT/Enhancer binding protein &beta regulates expression of the cystatin-related epididymal spermatogenic (Cres) gene. Biol. Reprod. 65:1452-1461. [PubMed]
Cornwall, G.A., Collis, R., Xiao, Q., Hsia, N., and Hann, S.R. (2001). B-Myc, a member of the myc family of transcriptional regulatory proteins, is predominantly expressed in the proximal caput epididymidis and is highly dependent on androgens and testicular factors for expression. Biol. Reprod. 64:1600-1607. [PubMed]
