Normal germ cell development is critical for reproductive health, as well as to ensure healthy offspring and prevent congenital birth defects. Currently, little is known about how gene expression is regulated in fetal male germ cells. Expanding our knowledge of germ cell translational control will aid in the understanding of environmental influences that contribute to the recent increase in testicular dysgenesis syndrome, a spectrum of male reproductive disorders such as carcinoma in situ, testicular cancer, cryptorchidism, and hypospadia that originate during this fetal period of germ cell development. The control of mRNA translation is essential for fetal male germ cel (gonocyte) development. Specific RNA binding proteins are required to block meiotic initiation and maintain gonocytes in a quiescent state prior to their transition to spermatogonia after birth. Little is known about the proteins or mechanisms that mediate translational control during this period. The lack of known target mRNAs for such binding proteins has impeded the investigation of translational control mechanisms. We have recently identified such a target in the reproductive homeobox gene, Rhox13, which is transcribed but not translated in gonocytes of the fetal mouse testis. RHOX13 protein expression is repressed by NANOS2 in the fetal testis and stimulated by retinoic acid (RA) in the neonatal testis. We will utilize Rhox13 and the fetal to neonatal male germ cel transition as a model system to determine the mechanisms by which mRNAs in the fetal testis are repressed but then move to a translating state in response to RA in the neonatal testis. Our results will significantly advance understanding of translational repression and RA-modulated gene regulation during male germ cell development. Results from this work will guide our design of a genome-wide translational state array analysis to reconcile global differences between the transcriptome and proteome of the fetal and neonatal testis.

Public Health Relevance

Normal germ cell development is critical for reproductive health, as well as to ensure healthy offspring and prevent congenital birth defects. Currently, little is known about how gene expression is regulated in fetal male germ cells. Expanding our knowledge of germ cell translational control will aid in the understanding of environmental influences that contribute to the recent increase in testicular dysgenesis syndrome, a spectrum of male reproductive disorders such as carcinoma in situ, testicular cancer, cryptorchidism, and hypospadia that originate during this fetal period of germ cell development. !

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15HD072552-01
Application #
8287403
Study Section
Special Emphasis Panel (ZRG1-EMNR-S (90))
Program Officer
Moss, Stuart B
Project Start
2012-05-07
Project End
2015-04-30
Budget Start
2012-05-07
Budget End
2015-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$432,837
Indirect Cost
$132,936
Name
East Carolina University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Busada, Jonathan T; Velte, Ellen K; Serra, Nicholas et al. (2016) Rhox13 is required for a quantitatively normal first wave of spermatogenesis in mice. Reproduction 152:379-88
Busada, Jonathan T; Geyer, Christopher B (2016) The Role of Retinoic Acid (RA) in Spermatogonial Differentiation. Biol Reprod 94:10
Mutoji, Kazadi; Singh, Anukriti; Nguyen, Thu et al. (2016) TSPAN8 Expression Distinguishes Spermatogonial Stem Cells in the Prepubertal Mouse Testis. Biol Reprod :
Hermann, Brian P; Mutoji, Kazadi N; Velte, Ellen K et al. (2015) Transcriptional and translational heterogeneity among neonatal mouse spermatogonia. Biol Reprod 92:54
Busada, Jonathan T; Chappell, Vesna A; Niedenberger, Bryan A et al. (2015) Retinoic acid regulates Kit translation during spermatogonial differentiation in the mouse. Dev Biol 397:140-9
Niedenberger, Bryan A; Busada, Jonathan T; Geyer, Christopher B (2015) Marker expression reveals heterogeneity of spermatogonia in the neonatal mouse testis. Reproduction 149:329-38
Busada, Jonathan T; Niedenberger, Bryan A; Velte, Ellen K et al. (2015) Mammalian target of rapamycin complex 1 (mTORC1) Is required for mouse spermatogonial differentiation in vivo. Dev Biol 407:90-102
Busada, Jonathan T; Kaye, Evelyn P; Renegar, Randall H et al. (2014) Retinoic acid induces multiple hallmarks of the prospermatogonia-to-spermatogonia transition in the neonatal mouse. Biol Reprod 90:64
Overcash, Ryan F; Chappell, Vesna A; Green, Thomas et al. (2013) Androgen signaling promotes translation of TMEFF2 in prostate cancer cells via phosphorylation of the * subunit of the translation initiation factor 2. PLoS One 8:e55257
Chappell, Vesna A; Busada, Jonathan T; Keiper, Brett D et al. (2013) Translational activation of developmental messenger RNAs during neonatal mouse testis development. Biol Reprod 89:61