Aleksandar Rajkovic, MD, PhD

Professor, Marcus Allen Hogge Chair in Reproductive Sciences, Director of Reproductive Genetics, Department of Obstetrics, Gynecology and Reproductive Sciences

Research

Our overall interests lie in the basic and translational research in the area of reproductive genetics. We are interested in understanding mechanisms that underlie normal developmental control of the reproductive tract and how developmental disruption leads to infertility, menopause, tumorigenesis, and accelerated aging.

 

Specific Areas of Research

Ovarian Development and failure

Germ cells carry the history of our generation(s) and are unique in their biology as well as of utmost importance in propagation and causation of genetic disorders. Their uniqueness is also reflected in unique mechanisms and molecules that govern their differentiation and growth. We are particularly interested in understanding transcriptional regulation of ovarian follicle activation and oocyte survival. Early stages of ovarian follicle formation, beginning with the breakdown of germ cell cysts, formation of primordial follicles and transition to primary and secondary follicles, are critical in determining the reproductive life span and fertility. Transcription of numerous germ cell specific genes, necessary and essential for follicular development, is initiated during these early stages of follicle formation. These transcription factors are necessary to drive oocyte growth, and synthesis of maternal effect genes that determine early embryogenesis and are likely involved in setting of epigenetic marks. We discovered novel germ cell specific transcriptional regulators Sohlh1, Sohlh2, Lhx8, and Nobox.
We also discovered that mutations in oocyte-specific transcriptional regulators such as Noboxand Figla associate with premature ovarian failure, emphasizing the importance of these pathways to women’s health. Sohlh1 and Sohlh2 are basic helix-loop-helix transcriptional regulators that suppress primordial follicle activation (PFA), and Sohlh1 and Sohlh2 deletions cause rapid PFA and oocyte loss. LHX8, a highly conserved LIM homeodomain protein, is located downstream of SOHLH1 and SOHLH2, and also represses primordial follicle activation. SOHLH1, SOHLH2 and LHX8 are uniquely expressed in the germline, and their deficiency affects gonadal development. We have a conditional knockout of Lhx8 and other tools to study how this pathway regulates postnatal folliculogenesis. We are currently using Lhx8 as a model system to understand oocyte-specific repression of follicle activation. Conditional deficiency of Lhx8 in oocytes of primordial follicles, leads to massive primordial follicle activation and premature oocyte depletion. We are studying the Lhx8 cross talk with the PI3K-AKT/mTORC1 dependent pathways as well as novel, PI3K-AKT/mTORC1 independent pathways. We are also studying the importance of oocyte-specific pathways at different stages of folliculogenesis and ovarian development, as well as promoters that LHX8 directly binds and regulates. Our laboratory also discovered HORMAD1, a major meiotic checkpoint in both male and female germline development. Unlike other meiotic checkpoints, HORMAD1 deficiency does not affect female germline nor gonadal development, as expected from a true checkpoint. Unlike other checkpoints, the ovaries in these animals are completely normal, with normal ovulation but absolute infertility due to embryo aneuploidy. Our findings show that meiosis and oocyte differentiation and survival are independent of each other, and we are studying the embryonic pathways of oocyte activation and differentiation.

In addition to uncovering mechanisms of oogenesis, we are interested in exploiting tissue-specific pathways to modulate fertility and reproductive life span and measure ovarian reserves. We are developing diagnostics to accurately measure primordial follicle reserves.

 

Genetics of Human Gonadal Failure

Primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), affects 1-4% of women, and is clinically defined as a cessation of menses prior to age 40 (normal being 50-52), with elevated follicle stimulating hormone (FSH) levels and low serum estradiol levels. Women with POI present with amenorrhea (loss of menstruation), either primary (never had one) or secondary (menstruated at one point, but stopped), hot flashes, and vaginal dryness prior to age 40. A long term consequence of POI is 50% higher overall mortality as compared to women who reach natural menopause, with an 80% increase in mortality due to ischemic heart disease and an increased risk of cognitive impairment and dementia, as well as premature osteoporosis. There are major gaps in our knowledge regarding the genetics, natural history, and medical management of primary ovarian insufficiency. Reliable biomarkers that can predict reproductive life span and ovarian failure are needed. Cryopreservation techniques of ovarian tissue and oocytes have advanced tremendously, and offer fertility preservation options to women at risk for premature loss of ovarian function. There is a great need to identify women who are at risk for ovarian failure, and who can benefit from advanced fertility preservation technologies.

Our laboratory is interested in determining genetic markers of ovarian aging. We are recruiting women who were diagnosed with ovarian insufficiency/failure prior to age 30, and whose cause of ovarian failure is unknown. Please visit our website if interested in enrollment at http://www.mwrif.org/165/genetic-basis-of-female-fertility-and-premature-ovarian-failure. We are sequencing genomes of these individuals in search of genetic markers of ovarian aging. We already determined that genes such as NOBOX, FIGLA, MCM8, and MCM9 are mutated in a subset of women with premature ovarian failure, and we know that many other genes are likely involved. We hope to identify a set of genetic markers that are strongly predictive of rapid ovarian aging.

If you think you may have Premature Ovarian Insufficiency and would like to be involved in our study, please contact us at pofstudy@mwri.magee.edu.

 

Uterine Leiomyomas

Uterine leiomyomas, better known as fibroid tumors, are clinically apparent in nearly 25% of women by age 45, and they cause major morbidity in American women. More than 200,000 surgeries are performed each year to either remove the leiomyomatous tumors (myomectomy) or the entire uterus (hysterectomy). Approximately half of all leiomyomas are asymptomatic, while the rest cause pelvic pressure and pain, irregular and heavy bleeding, anemia, premature labor and infertility. These symptoms are intensified by the common occurrence of multiple tumors within a single uterus, often necessitating surgical intervention. We have discovered microdeletions and duplications that associate with this tumor. We also discovered that 70% of American women harbor mutations within one gene, MED12, regardless of the karyotype abnormality of the tumors. We are currently investigating the mechanisms of MED12 action in leiomyomas and therapies directed towards eliminating such tumors in symptomatic women.

 

Visit the Rajkovic Lab website at http://rajkoviclab.org/.

Selected Publications

  • Mittal P, Shin YH, Yatsenko SA, Castro CA, Surti U, Rajkovic A. (2015) Med12 gain-of-function mutation causes leiomyomas and genomic instability. J Clin Invest. 2015 Aug 3;125(8):3280-4
  • Yatsenko AN, Georgiadis AP, Röpke A, Berman AJ, Jaffe T, Olszewska M, Westernströer B, Sanfilippo J, Kurpisz M, Rajkovic A, Yatsenko SA, Kliesch S, Schlatt S, Tüttelmann F. (2015) X-Linked TEX11 Mutations, Meiotic Arrest, and Azoospermia in Infertile Men. N Engl J Med. 2015 May 28; 372 (22): 2097-107.
  • Katari S, Wood-Trageser MA, Jiang H, Kalynchuk E, Muzumdar R, Yatsenko SA, Rajkovic A. (2015) Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin with Premature Ovarian Failure. J Clin Endocrinol Metab. 2015 Jun;100(6):2154-7. PMID: 25875778.
  • Ren Y, Suzuki H, Jagarlamudi K, Golnoski K, McGuire M, Lopes R, Pachnis V, Rajkovic A. (2015) Lhx8 regulates primordial follicle activation and postnatal folliculogenesis. BMC Biol. 2015 June 16;13(1):39.
  • Chen CT, Liu CT, Woods NF, Taylor HA, Zhao W, Zheng W, Evans MK, Harris TB, Henderson BE, Kardia SL, Kooperberg C, Liu Y, Mosley TH, Psaty B, Wellons M, Windham BG, Zonderman AB, Cupples LA, Demerath EW, Haiman C, Murabito JM, Rajkovic A. (2014) Meta-analysis of loci associated with age at natural menopause in African-American women. Hum Mol Genet. Jun 15; 23(12):3327-42.
  • Wood-Trageser MA, Gurbuz F, Yatsenko SA, Jeffries EP, Kotan LD, Surti U, Ketterer DM, Matic J, Chipkin J, Jiang H, Trakselis MA, Topaloglu AK, Rajkovic A. (2014) MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet Dec 4;95(6):754-62.
  • AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, Jeffries EP, Surti U,Ketterer DM, Afzal S, Ramzan K, Faiyaz-Ul Haque M, Jiang H, Trakselis MA, Rajkovic A. (2014) Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest. Jan;125(1):258-62
  • McGuire MM, Yatsenko A, Hoffner L, Jones M, Surti U, Rajkovic A. (2012) Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PLoS One. 2012; 7(3):e33251. PubMed PMID: 22428002; PubMed Central PMCID: PMC3299761
  • Suzuki H, Ahn, HW, Chu T, Bowden W, Gassei K, Orwig KE, Rajkovic A. (2012) SOHLH1 and SOHLH2 coordinate spermatogonial differentiation. Dev Biol. Jan 15;361(2):301-12.
  • Shin Y, Choi Y, Erdin SU, Yatsenko SA, Kloc M, Yang F, Wang PJ, Meistrich ML, Rajkovic, A (2010) Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in Mammalian meiosis, PLoS. Genet. Nov4:6(11):e1001190. PMCID: PMC2973818
  • Pangas S, Choi Y, Ballow D, Zhao Y, Westphal H, Matzuk M, Rajkovic A. (2006) Oogenesis requires germ cell-specific transcriptional regulators SOHLH1 and LHX8. Proc Natl Acad Sci U.S.A. 2006 May; 103(21): 8090-5.
  • Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM. (2004) NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science. 2004 Aug; 305(5687):1157-9. PubMed PMID: 15326356.

For additional publications, see: http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/48797626/?sort=date&direction=descending

 

Links

  • PITT – The University of Pittsburgh is a state-related research university, founded as the Pittsburgh Academy in 1787.
  • PREMATURE OVARIAN FAILURE STUDY – The University of Pittsburgh is now recruiting patients for their research study that involves looking for Genetic links that may reveal a cause to Premature Ovarian Failure (POF). Our laboratory is interested in determining genetic markers of ovarian aging. We are recruiting women who were diagnosed with ovarian insufficiency/failure prior to age 30, and whose cause of ovarian failure is unknown. Please visit our website if interested in enrollment at http://www.mwrif.org/165/genetic-basis-of-female-fertility-and-premature-ovarian-failure. We are sequencing genomes of these individuals in search of genetic markers of ovarian aging. We already determined that genes such as Nobox and Figla are mutated in some women with premature ovarian failure, and we know that many other genes are likely involved. We hope to identify a set of genetic markers that are strongly predictive of rapid ovarian aging. If you think you may have Premature Ovarian Insufficiency and would like to be involved in our study, please contact Kayla Golnoski at pofstudy@mwri.magee.edu.