Kenn Albrecht, Ph.D.
Assistant Professor of Medicine
Assistant Professor of Genetics and Genomics
Director of Transgenic Core Facility
Boston University School of Medicine
Post-doctoral Fellow, The Jackson Laboratory
1993 Ph.D. Genetics, The University of Connecticut
1986 B.S. Biology, SUNY Stony Brook
Mammalian gonadal sex determination is a powerful system for studying organogenesis, cell fate determination, and the evolution of sex chromosomes and developmental regulatory mechanisms. Besides basic scientific interest, mammalian sex determination also is of biomedical interest. Approximately one in 1000 infants has a gonadal or genital anomaly. Furthermore, many of the known genes involved in sex determination also are implicated in pathological processes such as tumorigenesis and primary adrenal failure, and have essential roles in the normal development of organs other than the gonads. We use the mouse as a model system for studying mammalian sex determination and gonad organogenesis and employ genetic, molecular genetic, genomic, cell biological and embryological techniques.
In mammals, XY fetuses develop testes due to the action of the Y-linked testis determining gene Sry (sex-determining region, Y chromosome) and XX fetuses develop ovaries in its absence. SRY is a DNA binding protein, and is likely a transcription factor that regulates other genes in the sex determination pathway. The mammalian gonadal precursors (the genital ridges) are bipotential and capable of differentiating as either testes or ovaries. It is generally accepted that each genital ridge contains a complete set of lineage precursors that are capable of adopting an ovarian or testicular cell-type fate. This “common precursor” hypothesis is best viewed as a series of bipotential cell fate decisions within the four cell lineages that comprise the gonad: germ cells, connective tissue cells, steroid producing cells and supporting cells. The current model proposes that Sry expression in the genital ridge initiates testis development by directing supporting cell precursors to develop as Sertoli rather than granulosa cells and that the development of all other gonadal cell types is dependent on the differentiation of the supporting cell lineage. Besides Sertoli cell differentiation, two direct consequences of Sry expression are the initiation of a male specific pattern of cell proliferation and the induction of mesenchymal cell migration from the adjacent mesonephros into the developing testis, a process necessary for testis cord development.
Although it is clear that expression of Sry is the trigger for testis differentiation, the molecular mechanisms of Sry function remain an enigma. For example, no downstream SRY target genes have been unequivocally identified and the regulation of Sry expression remains largely unexplored. A number of genes involved in gonadogenesis and sex determination have been identified and characterized; however, the position and relationship of these genes within the pathway remain to be defined and many more genes remain to be discovered. For example, most of the identified genes are transcription factors and not effector molecules. Additionally, our understanding of the genes involved in ovary development is particularly thin. Our future studies will include investigating the regulation of Sry expression, defining the position and relationship of known genes and identifying new genes in the gonad differentiation and sex determination pathways, and exploring basic mechanisms of gonad differentiation.
- Wake C, Labadorf A, Dumitriu A, Hoss AG, Bregu J, Albrecht KH, DeStefano AL, Myers RH. Novel microRNA discovery using small RNA sequencing in post-mortem human brain. BMC Genomics. 2016 Oct 04; 17(1):776. PMID: 27716130.Read at: PubMed
- Correa SM, Washburn LL, Kahlon RS, Musson MC, Bouma GJ, Eicher EM, Albrecht KH. Sex reversal in C57BL/6J XY mice caused by increased expression of ovarian genes and insufficient activation of the testis determining pathway. PLoS Genet. 2012; 8(4):e1002569. PMID: 22496664.Read at: PubMed
- Pazin DE, Albrecht KH. Developmental expression of Smoc1 and Smoc2 suggests potential roles in fetal gonad and reproductive tract differentiation. Dev Dyn. 2009 Nov; 238(11):2877-90. PMID: 19842175.Read at: PubMed
- Lee HJ, Pazin DE, Kahlon RS, Correa SM, Albrecht KH. Novel markers of early ovarian pre-granulosa cells are expressed in an Sry-like pattern. Dev Dyn. 2009 Apr; 238(4):812-25. PMID: 19301398.Read at: PubMed
- Liu P, Pazin DE, Merson RR, Albrecht KH, Vaziri C. The developmentally-regulated Smoc2 gene is repressed by Aryl-hydrocarbon receptor (Ahr) signaling. Gene. 2009 Mar 15; 433(1-2):72-80. PMID: 19146932.Read at: PubMed
- Liu L, Brown D, McKee M, Lebrasseur NK, Yang D, Albrecht KH, Ravid K, Pilch PF. Deletion of Cavin/PTRF causes global loss of caveolae, dyslipidemia, and glucose intolerance. Cell Metab. 2008 Oct; 8(4):310-7. PMID: 18840361.Read at: PubMed
- Izvolsky KI, Lu J, Martin G, Albrecht KH, Cardoso WV. Systemic inactivation of Hs6st1 in mice is associated with late postnatal mortality without major defects in organogenesis. Genesis. 2008 Jan; 46(1):8-18. PMID: 18196599.Read at: PubMed
- Bouma GJ, Washburn LL, Albrecht KH, Eicher EM. Correct dosage of Fog2 and Gata4 transcription factors is critical for fetal testis development in mice. Proc Natl Acad Sci U S A. 2007 Sep 18; 104(38):14994-9. PMID: 17848526.Read at: PubMed
- Thevenet L, Albrecht KH, Malki S, Berta P, Boizet-Bonhoure B, Poulat F. NHERF2/SIP-1 interacts with mouse SRY via a different mechanism than human SRY. J Biol Chem. 2005 Nov 18; 280(46):38625-30. PMID: 16166090.Read at: PubMed
- Bouma GJ, Albrecht KH, Washburn LL, Recknagel AK, Churchill GA, Eicher EM. Gonadal sex reversal in mutant Dax1 XY mice: a failure to upregulate Sox9 in pre-Sertoli cells. Development. 2005 Jul; 132(13):3045-54. PMID: 15944188.Read at: PubMed
Richard H. Myers, Ph.D.
Professor of Neurology & Medicine
1980 Post-doctoral., Human Genetics, Emory University, Atlanta, GA
1979 Ph.D., Behavior Genetics, Georgia State University, Atlanta, GA
1976 M.A., Psychology, Georgia State University, Atlanta, GA
1969 B.A. Psychology, University of Kansas, Lawrence, KS
My professional interests have focused upon the application of genetic research methods for the investigation of adult onset diseases with complex etiology (Parkinson’s disease, coronary heart disease, Alzheimer’s disease, pulmonary function, osteoarthritis, osteoporosis etc.). I have a long-standing interest in Huntington’s disease and have participated in a wide range of research investigations for this disease. I have been a member of the New England Huntington’s disease “Center Without Walls” since its inception in 1980. My HD studies may best be characterized as ‘Neurobiological Studies’ in that they include studies into the mechanisms of disease expression, including complex genetic modifier studies and a series of neuropathological studies of effects of disease expression in the brain. Additional interests are in the ethical issues influencing utilization of genetic test procedures.
I have been involved in a number of studies in positional cloning. I participated in the cloning of the gene for Huntington’s disease in 1993. I initiated the genome scan project in the Framingham Study, and a genome scan in Parkinson’s disease. My Parkinson’s disease genetic linkage study, known as the “GenePD” study, involves an international collaboration of twenty clinical centers in Parkinson’s disease. The study is seeking genetic loci involved in risk for PD. Since 1993 I have participated in genetic linkage studies for hypertension (the HyperGEN study, one of the NHLBI Family Blood Pressure Program Project studies), and the genome scan in the NHLBI Family Heart Study.
- Labadorf A, Choi SH, Myers RH. Evidence for a pan-neurodegenerative disease response in Huntington’s disease and Parkinson’s disease expression profiles. Frontiers in Molecular Neuroscience. 11 January 2018 | https://doi.org/10.3389/fnmol.2017.00430
- Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N, Hsu N-Y, Chuang L-S, Carmi S, Villaverde N, Li X, Rivas M, Levine AP, Bao X, Labrias PR, Haritunians T, Ruane D, Gettler K, Chen E, Schiff ER, Pontikos N, Barzilai N, Brant SR, Bressman S, Cheifetz AS, Clark LN, Daly MJ, Desnick R, Duerr RH, Katz S, Lencz T, McGovern DPB, Myers RH, Ostrer H, Ozelius L, Payami H, Peter Y, Rioux JD, Segal A, Scott WK, Silverberg MS, Vance JM, Foroud T, Atzmon G, Pe’er I, Ioannou Y, Yue Z, Schadt EE, Cho JH, Â Peter I.Â Functional Variants in LRRK Confer Pleiotropic Effects on Crohn’s Disease and Parkinson’s Disease Risk. Science Translational Medicine. 10, eaai7795, 2018.
- Reed ER, Latourelle JC, Bockholt JH, Bregu J, Smock J, Paulsen JS, PhD, Myers RH, and the PREDICT-HD CSF ancillary study investigators. MicroRNAs in CSF as prodromal biomarkers for Huntington’s disease in the PREDICT-HD Study. Neurology. 2017 Dec 27 (PMID: 29282329).
- Lee JM, Chao MJ, Harold D, Abu Elneel K, Gillis T, Holmans P, Jones L, Orth M, Myers RH, Kwak S, Wheeler VC, MacDonald ME, Gusella JF. A modifier of Huntington’s disease onset at the MLH1 locus. Hum Mol Genet. 2017 Oct 01; 26(19):3859-3867. (PMID: 28934397).
- Chao MJ, Gillis T, Atwal R, Mysore JS, Arjomand J, Harold D, Holmans P, Jones L, Orth M, Myers RH, Kwak S, Wheeler VC, MacDonald ME, Gusella JF, Lee J-M. Haplotype-based stratification of Huntington’s disease. European Journal of Human Genetics. 2017 Aug 23. (PMID: 28832564).
- Neueder A, Landles C, Ghosh R, Howland D, Myers RH, Faull RLM, Tabrizi SJ, Bates GP. The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntingtonâ€™s disease patients. Scientific Reports2017;7:1307- DOI:10.1038/s41598-017-01510-z. (PMID:28465506; PMCID: PMC3568346).
- Choi SH, Labadorf AT, Myers RH, Lunetta KL, Dupuis J, DeStefano AL. Evaluation of Logistic Regression Models and Effect of Covariates for Case-Control Study in RNA-Seq Analysis. BMC Bioinformatics 2017; 18:91DOI 10.1186/s12859-017-1498-y. (PMID:28166718; PMCID:PMC5294900).
- Trinh J, Gustavsson EK, Vilarino-Guell C, Bortnick S, Latourelle J, McKenzie MB, Tu CS, Nosova E, Khinda J, Milnerwood A, Lesage S, Brice A, Tazir M, Aasly JO, Parkkinen L, Haytural H, Foroud T, Myers RH, Sassi SB, Hentati E, Nabli F, Farhat E, Amouri R, Hentati F, Farrer MJ. DNM3 and genetic modifiers of age of onset in LRRK2 Gly2019Ser Parkinsonism: a genome-wide linkage and association study. Lancet Neurology. 2016 Nov; 15(12):1248-1256. (PMID: 27692902).
- Bates G, Osborne GF, Ali N, Benjamin AC, Papadopoulou AS, Howland D, Tabrizi SJ, Faull RLM, Myers RH, Landles C, Neueder A. B4 Detection of the aberrantly spliced exon 1 – intron 1 htt mRNA in HD patient post mortem brain tissue and fibroblast lines. Journal of Neurology Neurosurgery & Psychiatry 87(Suppl 1):A10.2-A10· September 2016.
- Wake C, Labadorf A, Dumitriu A. Hoss AG, Bregu J, Albrecht KH, DeStefano AL, Myers RH. Novel microRNA discovery using small RNA sequencing in post-mortem human brain. BMC Genomics. 2016; 17:776, DOI 10.1186/s12864-016-3114-3. (PMID:27716130; PMCID:PMC5050850).