The National Institute of Diabetes & Digestive & Kidney Diseases

We use the mouse as a paradigm for investigating the developmental biology of female gonadogenesis and early embryogenesis. In particular, we study molecular mechanisms used by oocyte-specific, maternal factors to promote folliculogenesis, ensure fertilization, and sustain cleavage-stage development. Projects include:

Folliculogenesis: At birth the ovary contains its full complement of germ cells, each surrounded by a single layer of granulosa cells which together form primordial follicles. We have identified a novel, oocyte-specific, basic helix-loop-helix transcription factor, FIGLA (factor in the germline, alpha). The single-copy Figla gene has been disrupted in embryonic stem cells and these cells have been used to establish mouse lines. Female mice lacking FIGLA are sterile because of germ cell depletion secondary to an inability to form primordial follicles perinatally. Identification of downstream targets of FIGLA should provide additional insights into the molecular basis of follicle formation.

Fertilization: Three zona glycoproteins (ZP1, ZP2, ZP3) are secreted during folliculogenesis to form the zona pellucida, an extracellular matrix that mediates sperm binding to the egg and induces sperm acrosome exocytosis. Historically, both binding and induction of the acrosome reaction have been attributed to a zona ligand binding to a sperm surface receptor. However, we have developed models in which sperm-egg recognition is predicated on the cleavage status of ZP2 and penetration of the zona matrix is required for the acrosome reaction. Molecular biology and transgenesis are being used to validate these models of sperm-egg recognition and acrosome exocytosis.

Early Development: We have identified a subcortical maternal complex (SCMC) that is required for cleavage-stage embryogenesis. Members of the complex include FLOPED (factor located in oocytes permitting embryonic development), TLE6 (a Groucho-like co-repressor), MATER (maternal antigen that embryos require) and a binding partner, Filia. Embryos derived from Floped or Mater null eggs, do not progress beyond the 2-cell stage and are sterile; null embryos from other components of the complex have impaired cleavage stage progression and decreased fecundity. Efforts are underway to define the molecular basis of these maternal effect phenotypes.

Fellowships are available. A strong background in molecular biology and a keen interest in cell/developmental biology are required. Candidates should be highly motivated with less than 5 years of post-doctoral experience. Please send: 1) a current curriculum vitae and bibliography; 2) a statement of long-term career goals; and 3) three letters of reference.

1. Li L, Baibakov, B and Dean J A subcortical maternal complex essential for pre-implantation mouse embryogenesis Dev. Cell: 416-425, 2008.

2. Ohsugi, M, Zheng, P, Baibakov, B, Li L and Dean J Maternally derived FILIA/MATER complex localizes asymmetrically in cleavage stage mouse embryos Development(135): 259-69, 2008. [Full Text/Abstract]

3. Zheng P, Dean J Oocyte-specific genes affect folliculogenesis, fertilization, and early development. Semin Reprod Med (25): 243-51, 2007. [Full Text/Abstract]

4. Joshi S, Davies H, Sims LP, Levy SE, Dean J Ovarian gene expression in the absence of FIGLA, an oocyte-specific transcription factor. BMC Dev Biol (7): 67, 2007. [Full Text/Abstract]

5. Baibakov B, Gauthier L, Talbot P, Rankin TL, Dean J Sperm binding to the zona pellucida is not sufficient to induce acrosome exocytosis. Development (134): 933-43, 2007. [Full Text/Abstract]

6. Hoodbhoy T, Aviles M, Baibakov B, Epifano O, Jimenez-Movilla M, Gauthier L, Dean J ZP2 and ZP3 traffic independently within oocytes prior to assembly into the extracellular zona pellucida. Mol Cell Biol (26): 7991-8, 2006. [Full Text/Abstract]

7. Hoodbhoy T, Joshi S, Boja ES, Williams SA, Stanley P, Dean J Human sperm do not bind to rat zonae pellucidae despite the presence of four homologous glycoproteins. J Biol Chem (280): 12721-31, 2005. [Full Text/Abstract]

8. Zhao M, Boja ES, Hoodbhoy T, Nawrocki J, Kaufman JB, Kresge N, Ghirlando R, Shiloach J, Pannell L, Levine RL, Fales HM, Dean J Mass spectrometry analysis of recombinant human ZP3 expressed in glycosylation-deficient CHO cells. Biochemistry (43): 12090-104, 2004. [Full Text/Abstract]

9. Dean J Reassessing the molecular biology of sperm-egg recognition with mouse genetics. Bioessays (26): 29-38, 2004. [Full Text/Abstract]

10. Rankin TL Coleman JS Epifano O Hoodbhoy T Turner SG Castle PE Lee E Gore-Langton R Dean J Fertility and taxon-specific sperm binding persist after replacement of mouse sperm receptors with human homologs. Dev Cell (5): 33-43, 2003. [Full Text/Abstract]

11. Zhao M Gold L Dorward H Liang LF Hoodbhoy T Boja E Fales HM Dean J Mutation of a conserved hydrophobic patch prevents incorporation of ZP3 into the zona pellucida surrounding mouse eggs. Mol Cell Biol (23): 8982-91, 2003. [Full Text/Abstract]

12. Boja ES Hoodbhoy T Fales HM Dean J Structural characterization of native mouse zona pellucida proteins using mass spectrometry. J Biol Chem (278): 34189-202, 2003. [Full Text/Abstract]

13. Zhao M Gold L Ginsberg AM Liang LF Dean J Conserved furin cleavage site not essential for secretion and integration of ZP3 into the extracellular egg coat of transgenic mice. Mol Cell Biol (22): 3111-20, 2002. [Full Text/Abstract]

14. Epifano O Dean J Genetic control of early folliculogenesis in mice. Trends Endocrinol Metab (13): 169-73, 2002. [Full Text/Abstract]

15. Rankin TL O''Brien M Lee E Wigglesworth K Eppig J Dean J Defective zonae pellucidae in Zp2-null mice disrupt folliculogenesis, fertility and development. Development (128): 1119-26, 2001. [Full Text/Abstract]

16. Takasaki N Rankin T Dean J Normal gonadal development in mice lacking GPBOX, a homeobox protein expressed in germ cells at the onset of sexual dimorphism. Mol Cell Biol (21): 8197-202, 2001. [Full Text/Abstract]

17. de Vries WN Binns LT Fancher KS Dean J Moore R Kemler R Knowles BB Expression of Cre recombinase in mouse oocytes: a means to study maternal effect genes. Genesis (26): 110-2, 2000. [Full Text/Abstract]

18. Soyal SM Amleh A Dean J FIGalpha, a germ cell-specific transcription factor required for ovarian follicle formation. Development (127): 4645-54, 2000. [Full Text/Abstract]

19. Takasaki N McIsaac R Dean J Gpbox (Psx2), a homeobox gene preferentially expressed in female germ cells at the onset of sexual dimorphism in mice. Dev Biol (223): 181-93, 2000. [Full Text/Abstract]

20. Tong ZB Nelson LM Dean J Mater encodes a maternal protein in mice with a leucine-rich repeat domain homologous to porcine ribonuclease inhibitor. Mamm Genome (11): 281-7, 2000. [Full Text/Abstract]

21. Tong ZB Gold L Pfeifer KE Dorward H Lee E Bondy CA Dean J Nelson LM Mater, a maternal effect gene required for early embryonic development in mice. Nat Genet (26): 267-8, 2000. [Full Text/Abstract]