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Physiology Faculty
Life Science III, Room 2071
Email: jmaclean@siumed.edu
- PHSL 410A/511A Mammalian Physiology (Cardiovascular Unit)
- PHSL 500 Advanced Seminar in Physiology
- PHSL 570Q Reproductive Physiology
- Medical Physiology Resource Sessions in Cardiovascular, Respiratory, and Renal (CRR) unit
- MSI Problem Based Learning tutor in CRR
- CRR Unit Coordinator
Homeobox genes encode transcription factors that regulate developmental processes. Virtually nothing was known about the role of homeobox genes in regulating postnatal reproductive processes until recently, when we identified a new cluster of homeobox genes that are good candidates to regulate reproductive development and physiology [Cell, 2005]. All of these Reproductive homeobox on the X chromosome (Rhox) genes are selectively expressed in reproductive tissues (testis, epididymis, ovary, and placenta). All but four of the 33 mouse Rhox genes are expressed in the female reproductive tract. While preliminary characterization of Rhox gene expression during development and function of the ovary suggests that the cluster is regulated by estrogen and/or progesterone, formal studies to investigate direct hormonal regulation of the Rhox genes have exclusively centered on androgen regulation. Indeed, targeted deletion of Rhox5, results in male subfertility due to increased germ-cell apoptosis and abnormal sperm motility. However, Rhox5-null females are fertile.
Since Rhox cluster members exhibit distinct as well as partially overlapping spatial, temporal, and quantitative collinear expression patterns in the cycling ovary, we believe that Rhox genes establish distinct developmental checkpoints during folliculogenesis. The long range goal of our research is to identify and characterize the transcriptional networks under control of each Rhox gene and to determine how these genes synergize to promote gonad development, germ cell differentiation, and ultimately fertility. Presently, we are preparing to investigate the role of RHOX8 in sex determination (i.e. specification of the testes in XY males), the role of RHOX8 in ovarian folliculogenesis via CRISP/Cas9 deletion, and the impact on male and female fertility following double ablation of Rhox5 and Rhox8. The first double RHOX mutant in any system.
Wayne CM, MacLean JA, Cornwall G, Wilkinson MF (2002) Two novel human X-linked homeobox genes, hPEPP1 and hPEPP2, selectively expressed in the testis. Gene 301: 1-11
MacLean JA, Chakrabarty A, Xie S, Bixby JA, Roberts RM, Green JA (2003) Family of Kunitz proteins from trophoblast: expression of the trophoblast Kunitz domain proteins (TKDP) in cattle and sheep. Molecular Reproduction and Development 65: 30-40
MacLean JA, Roberts RM, Green JA (2004) Atypical Kunitz-type serine proteinase inhibitors produced by the ruminant placenta. Biology of Reproduction 71: 455-463
MacLean JA, Rao MK, Doyle KM, Richards JS, Wilkinson MF (2005) Regulation of the Rhox5 homeobox gene in primary granulosa cells: preovulatory expression and dependence on SP1/SP3 and GABP. Biology of Reproduction 73: 1126-1134
Maclean JA, Wilkinson MF (2005) Gene regulation in spermatogenesis. Current topics in developmental biology 71: 131-197
Maclean JA, Chen MA, Wayne CM, Bruce SR, Rao M, Meistrich ML, Macleod C, Wilkinson MF (2005) Rhox: a new homeobox gene cluster. Cell 120: 369-382. Commentaries on this paper: a) Hogeveen KN, Sassone-Corsi P (2005). Homeobox Galore: When Reproduction Goes Rhox and Roll. Cell 120: 369-382. b) Spitz F, Duboule D (2005). Reproduction in Clusters. Nature 434:715-716
Chakrabarty A, MacLean JA, Hughes AL, Roberts RM, Green JA (2006) Rapid evolution of the trophoblast kunitz domain proteins (TKDPs)-a multigene family in ruminant ungulates. Journal of Molecular Evolution 63: 274-282
Rao MK, Pham J, Imam JS, MacLean JA, Murali D, Furuta Y, Sinha-Hikim AP, Wilkinson MF (2006) Tissue-specific RNAi reveals that WT1 expression in nurse cells controls germ cell survival and spermatogenesis. Genes & Development 20: 147-152
MacLean JA, Lorenzetti D, Hu Z, Salerno WJ, Miller J, Wilkinson MF (2006) Rhox homeobox gene cluster: recent duplication of three family members. Genesis 44: 122-129
Hu Z, MacLean JA, Bhardwaj A, Wilkinson MF (2007) Regulation and function of the Rhox5 homeobox gene. Annals of the New York Academy of Sciences 1120: 72-83
Hu Z, Shanker S, MacLean JA, Ackerman SL, Wilkinson MF (2008) The RHOX5 homeodomain protein mediates transcriptional repression of the netrin-1 receptor gene Unc5c. The Journal of Biological Chemistry 283: 3866-3876
Hayashi K, Erikson DW, Tilford SA, Bany BM, Maclean JA, Rucker EB, Johnson GA, Spencer TE (2009). Wnt genes in the mouse uterus: potential regulation of implantation. Biology of Reproduction 80: 989-1000
MacLean JA and Wilkinson MF (2010). The Rhox genes. Reproduction 140: 195-213
Chang YF, Lee-Chang JS, Panneerdoss S, MacLean JA, Rao MK (2011). Isolation of Sertoli, Leydig, and spermatogenic cells from the mouse testis. BioTechniques 51: 341-342, 344
Hayashi K, Yoshioka S, Reardon SN, Rucker EB, Spencer TE, DeMayo FJ, Lydon JP, and MacLean JA (2011). WNTs in the neonatal mouse uterus: potential regulation of endometrial gland development. Biology of Reproduction 84: 308-319
Maclean JA, Bettegowda A, Kim BJ, Lou CH, Yang SM, Bhardwaj A, Shanker S, Hu Z, Fan Y, Eckardt S, McLaughlin KJ, Skoultchi AI, and Wilkinson MF (2011). The Rhox homeobox gene cluster is imprinted and selectively targeted for regulation by histone h1 and DNA methylation. Molecular and Cellular Biology 31: 1275-1287
Yoshioka S, King ML, Ran S, Okuda H, Maclean JA, McAsey ME, Sugino N, Brard L, Watabe K, Hayashi K (2012). WNT7A regulates tumor growth and progression in ovarian cancer through the WNT/beta-catenin pathway. Mol Cancer Res 10(3):469-482
Reardon SN**, King ML, Maclean JA, Mann JL, Demayo FJ, Lydon JP, Hayashi K (2012). Cdh1 Is Essential for Endometrial Differentiation, Gland Development, and Adult Function in the Mouse Uterus. Biology of Reproduction 86(5):141, 1-10
MacLean JA, Hayashi K, Turner TT, Wilkinson MF (2012). The Rhox5 homeobox gene regulates the Region-Specific Expression of its paralogs in the rodent epididymis. Biology of Reproduction 86(6):189, 1-11. Commentary on this paper: Hammond GL (2012). Rhox5 rules in an evolving saga of
reproductive diversity. Biology of Reproduction 86(6):188, 1-2
MacLean JA (2013). The role of Rhox homeobox factors in tumorigenesis. Frontiers in Bioscience 18:474-92
Brown RM**, Davis MG*, Hayashi K, and MacLean JA (2013). Regulated expression of Rhox8 in the mouse ovary: evidence for the role of progesterone and RHOX5 in granulosa cells. Biology of Reproduction 88(5):126, 1-12. Commentary on this paper: Dias JA (2013). In the ovary, the Rhox library is the lender and some genes are the borrowers. Biology of Reproduction 88(5):127
Lindberg ME**, Stodden GR*, King ML, MacLean JA, Mann JL, DeMayo FJ, Lydon JP, and Hayashi K (2013). Loss of Cdh1 and Pten accelerates cellular invasiveness and angiogenesis in the mouse uterus. Biology of Reproduction 89:8. PMID: 23740945
MacLean JA, Hu Z, Welborn P*, Song HW, Rao MK, Wayne CM, and Wilkinson MF (2013). The RHOX homeodomain proteins regulate the expression of insulin and other metabolic regulators in the testis. J Biol Chem. 288(48):34809-25. PMC3843094
Stodden GR**, Lindberg ME**, King ML, Paquet M, MacLean JA, Mann JL, DeMayo FJ, Lydon JP, Hayashi K (2014). Loss of Cdh1 and Trp53 in the uterus induces chronic inflammation with modification of tumor microenvironment. Oncogene 34(19):2471-82 PMID: 24998851
King ML, Lindberg ME**, Stodden GR*, Okuda H, Ebers SD*, Johnson A, Montag A, Lengyel E, MacLean JA, and Hayashi K (2014). WNT7A/β-catenin signaling induces FGF1 and influences sensitivity to niclosamide in ovarian cancer. Oncogene 34(26):3452-62. PMID: 25174399
Welborn JP**, Davis MG**, Ebers SD*, Stodden GR**, Hayashi K, Cheatwood JL, Rao MK, and MacLean JA (2015). Rhox8 ablation in the Sertoli cells using a tissue-specific RNAi approach results in impaired male fertility in mice. Biology of Reproduction 93(1):8-16 PMID: 25972016
* SIU Undergraduate ** SIU Graduate Student