Gail A. Cornwall, Ph.D.
Reproductive biology; sperm maturation and epididymal function. Amyloidogenesis; pathological and functional amyloid in the male reproductive tract.
Functional role of the cystatin CRES in sperm maturation and fertilization.
The cystatin-related epididymal spermatogenic (CRES) protein defines a new subgroup within the family 2 of the cystatin superfamily of cysteine protease inhibitors. CRES and the seven other subgroup members exhibit reproductive-specific expression and lack consensus sites for cysteine protease inhibition suggesting functions distinct from that of typical family 2 cystatins. CRES is synthesized and secreted by the proximal caput epididymal epithelium and is present within the lumen surrounding the maturing spermatozoa suggesting roles in sperm maturation. CRES also localizes to the sperm acrosome suggesting a functional role during fertilization. In this project we are using a CRES gene knockout mouse model to determine CRES function within the epididymis and spermatozoa to ultimately gain a better understanding of the mechanisms of sperm maturation and fertilization.
Protein amyloidogenesis in the epididymis: mechanisms and biological signicance.
Proteins that misfold and form self-aggregates with a specific cross beta sheet fibrillar structure are known as amyloids. Although generally associated with neurodegenerative diseases such as Alzheimer’s and Huntington’s disease, amyloid structures have also recently been found to carry out biological roles in some mammalian tissues and thus are called functional amyloid. We have determined that CRES forms amyloid structures in vitro similar to that present in pathological conditions raising the possibility that CRES also forms amyloid in vivo within the epididymis. In this project we are studying CRES amyloid within the epididymal lumen to determine whether it may represent a functional amyloid. Alternatively, CRES amyloid may form a cytotoxic structure but mechanisms are in place to protect against cytotoxicity and prevent damage to spermatozoa during maturation.
- Do HQ, Hewetson A, Myers C, Khan NH, Hastert MC, M Harsini F, Latham MP, Wylie BJ,
Sutton RB, Cornwall G.A. (2019) The Functional Mammalian CRES (Cystatin-Related Epididymal Spermatogenic)
Amyloid Is Antiparallel β-Sheet Rich and Forms a Metastable Oligomer During Assembly.
Sci Rep. 2019 Jun 25;9(1):9210. doi: 10.1038/s41598-019-45545-w. PubMed
- Cornwall, G.A., Do HQ, Hewetson A, Muthusubramanian A, Myers C. (2019). The epididymal amyloid matrix: structure and putative functions. Andrology. Jan 20. doi: 10.1111/andr.12586. PubMed
- Hewetson A, Do HQ, Myers C, Muthusubramanian A, Sutton RB, Wylie BJ, Cornwall, G.A. (2017). Functional amyloids in reproduction. Biomolecules. 7(3). pii: E46. PubMed
- Whelly, S., Muthusubramanian A, Powell, J., Johnson, S., Hastert, M. C., and Cornwall, G.A. (2016). CRES (cystatin-related epididymal spermatogenic) subgroup members are part of an amyloid matrix and associated with extracellular vesicles in the mouse epididymal lumen. Mol Human Reprod 22:729-744. PubMed
- Egge, N., Muthusubramanian A, and Cornwall, G.A. (2015). Amyloid properties of the mouse egg zona pellucida. PLoS One. 2015 Jun 4;10(6):e0129907. doi: 10.1371/journal.pone.0129907. eCollection 2015. PubMed
- Cornwall, G.A. (2014). Role of posttranslational protein modifications in epididymal sperm maturation and extracellular quality control. Adv Exp Med Biol. 759:159-80. doi: 10.1007/978-1-4939-0817-2_8. Review. PubMed
- Guyonnet B., Egge N., and Cornwall, G.A. (2014). Functional amyloids in the mouse sperm acrosome. Mol Cell Biol. 34:2624-34. PubMed
- Whelly, S., Serobian G., Borchardt C., Powell, J., Johnson, S., Hakansson, K., Lindstrom, V., Abrahamson, M., Grubb, A., and Cornwall, G.A. (2014). Fertility defects in mice expressing the L68Q variant of human cystatin C:a role for amyloid in male infertility. J Biol Chem 14;289:7718-29. PubMed
- Ferrer, M., Cornwall, G.A., Oko, R. (2013). A population of CRES resides in the outer dense fibers of spermatozoa. Biol Reprod 88:1-9. PubMed
- Guyonnet, B., Zabet-Moghaddam, M., SanFrancisco, S., and Cornwall, G.A. (2012). Isolation and proteomic characterization of the mouse sperm acrosomal matrix. Mol Cell Proteomics 11:758-774. PubMed
- Whelly, S., Johnson, S.S., Powell, J., Borchardt C., Hastert, M-C, and Cornwall, G.A. (2012). Nonpathological extracellular amyloid is present during normal epididymal sperm maturation. Plos One, 10.1371/journal.pone.0036394. PubMed
- Tardif S., Guyonnet, B., Cormier, N., and Cornwall, G.A. (2012). Alteration in the processing of the ACRBP/sp32 protein and sperm head/acrosome
malformations in proprotein convertase 4 (PCSK4) null mice. Mol Human Reprod. 18:298-307.
Cover photo PubMed
- Cornwall, G.A., von Horsten, H.H., and Whelly, S. (2011). Cystatin-related epididymal spermatogenic aggregates in the epididymis. J. Androl.32:679-85. PubMed
- Chau, K. and Cornwall, G.A. (2011). Impaired fertility in vitro in mice lacking the cystatin CRES (cystatin-related epididymal spermatogenic): rescue by exposure of spermatozoa to dibutyryl cAMP/IBMX Biol Reprod. 84:140-52. PubMed
- Parent, A.D., Cornwall, G.A., Liu, L.Y., Smith, C.E., and Hermo, L. (2011). Alterations in the testis and epididymis associated with loss of function of the cystatin related epididymal spermatogenic (CRES) protein. J Androl 32; 444-63. PubMed
- Cornwall, G.A. (2009). New insights into epididymal biology and function. Human Reproduction Update 1;1-15.PubMed
- 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. 282:32912-32923. PubMed
- Cornwall, G.A., von Horsten HH, Swartz D, Johnson S, Chau K, Whelly S. Extracellular quality control in the epididymis. Asian J Androl (2007) 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
- 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
- Kirby, J.L., Yang, L., Labusm J.C., Lye, R.J., Hsia, N. Day, R., Cornwall, G.A., and Hinton, B.T. (2004). Characterization of epididymal epithelial cell-specific gene promoters by in vivo electroporation. Biol. Reprod. 71: 613-619.PubMed
- Hsia , N. and Cornwall, G.A. (2004) Microarray analysis of region-specific gene expression in the mouse epididymis. Biol. Reprod.70: 448-457.PubMed
- Cornwall, G.A., Cameron, A., Lindberg, I., Hardy, D., Cormier, N., and Hsia, N. (2003). CRES protein inhibits the serine protease prohormone convertase PC2. Endocrinology 144:901-908. 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
- Cooper TG, Wagenfeld A, Cornwall, G.A., Hsia N, Chu ST, Orgebin-Crist MC, Drevet J, Vernet P, Avram C, Nieschlag E, Yeung CH. (2003). Gene and protein expression in the epididymis of infertile c-ros receptor tyrosine kinase-deficient mice. Biol. Reprod. 69:1750-62. PubMed
- Hsia, N and Cornwall, G.A. (2003). Cres2 and Cres3: New members of the CRES subgroup of family 2 cystatins. Endocrinology 144:909-915. PubMed