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Microarray Analyses of Newborn Mouse Ovaries Lacking Nobox¹

Department of Obstetrics and Gynecology,³ Baylor College of Medicine, Houston, Texas 77030 Center for Reproductive Medicine,⁴ Shandong Provincial Hospital of Shandong University, Jinan, 250012, China Division of Genetics,⁵ Harvard University Graduate Biophysics Program,⁶ Department of Pathology,⁷ and Harvard/MIT Division of Health Sciences and Technology,⁸ Cambridge, Massachusetts 02138

ABSTRACT

Nobox is a homeobox gene expressed in oocytes and critical in oogenesis. Nobox deficiency leads to rapid loss of postnatal oocytes. Early oocyte differentiation is poorly understood. We hypothesized that lack of Nobox perturbs global expression of genes preferentially expressed in oocytes as well as microRNAs. We compared Nobox knockout and wild-type ovaries using Affymetrix 430 2.0 microarray platform. We discovered that 28 (74%) of 38 of the genes downregulated more than 5-fold in the absence of Nobox were preferentially expressed in oocytes, whereas only 5 (15%) of 33 genes upregulated more than 5-fold in the absence of Nobox were preferentially expressed in oocytes. Protein-binding microarray helped identify nucleotide motifs that NOBOX binds and that several downregulated genes contain within putative promoter regions. MicroRNA population in newborn ovaries deficient of Nobox was largely unaffected. Genes whose proteins are predicted to be secreted but were previously unknown to be significantly expressed in early oogenesis were downregulated in Nobox knockouts and included astacin-like metalloendopeptidase (Astl), Jagged 1 (Jag1), oocyte-secreted protein 1 (Oosp1), fetuin beta (Fetub), and R-spondin 2 (Rspo2). In addition, pluripotency-associated genes Pou5f1 and Sall4 are drastically downregulated in Nobox-deficient ovaries, whereas testes-determining gene Dmrt1 is overexpressed. Our findings indicate that Nobox is likely an activator of oocyte-specific gene expression and suggest that the oocyte plays an important role in suppressing expression of male-determining genes, such as Dmrt1.

follicular development,, folliculogenesis,, gamete biology,, microarray,, microRNA,, Nobox,, oocyte,, oocyte development,, oogenesis,, ovarian failure,, ovary,, transcription factor

¹Supported by grant HD044858, and a March of Dimes grant (6-FY05-70) to A.R.

Correspondence: ²Aleksandar Rajkovic, Department of Obstetrics and Gynecology, Baylor College of Medicine, 1709 Dryden Rd., Suite 1100, Houston, TX 77030. FAX: 713 798 2744; e-mail: rajkovic{at}bcm.edu