The role of the Fused toes locus containing Iroquois homeobox gene 3, 5, and 6 and Ftm, Fto, and Fts during ovary and testis development in mice

Fused toes locus;Homeobox genes;Primordial germ cells;ovarian and testis development;Communication between somatic and germ cells

Kim, Bong Ki

关键词: Fused toes locus;    Homeobox genes;    Primordial germ cells;    ovarian and testis development;    Communication between somatic and germ cells;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/17008/1_KIM_BONGKI.pdf?sequence=2&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

These studies were conducted for a greater understanding of the function of the Fused toes (Ft) locus, which includes six genes: homeobox genes: Irx3, Irx5 and Irx6 and three other genes: Fto, Fts, and Ftm, during male and female gonad development.Ft mutant mice are missing Ft locus genes whose function is unknown during male and female gonad development. These six missing genes show stage and sex specific expression patterns during sex determination and differentiation in mouse gonads. Irx3 and Irx5, which are the homeobox genes, and Ftm and Fts are highly expressed in ovaries from the stage of early gonad development. However, Ftm shows a dramatic increase in adult testes. This dimorphic expression pattern gave us the following central hypothesis. The Ft locus is a new potential gene cluster essential for normal ovarian and testis development. To elucidate this main hypothesis, I have conducted three serial studies 1) to investigate the function of the Ft locus in developing female gonads, 2) to examine the function of the Ft locus in developing male gonads, 3) to determine the functional roles of Irx3 and Irx5 during developing male and female gonads.In the first and second studies, Ft mutant mice were used to investigate functional roles of Ft locus. In the absence of the the Ft locus, the primordial germ cells (PGC) develop normally, however, many PGC fail to migrate to the genital ridge and fail to proliferate once they reach the genital ridge. Failure of the PGC migration and proliferation causes a significant reduction in the number of germ cells. In addition, the Ft mutant ovaries revealed a disruption in their follicle formation, as most follicles were blocked before secondary follicle formation. Also, a lower expression level of Foxl2, which is known as a key gene for normal follicle development, was observed in the Ft mutant granulosa cells. My second study was to investigate male testis development in the absence of the Ft locus. In the absence of the Ft locus, many PGC failed to arrive at the genital ridge and to proliferate described in the female gonad. Otherwise, fetal testis development was largely normal. After birth, however, I observed a failure of Sertoli cell maturation in Ft mutant testes. The Ft mutant testis showed a low level of MIS expression in the Sertoli cells and a partial failure of germ cell movement toward the basement membrane.The last study in the series was to begin to determine the function of Irx3 and Irx5 during male and female gonad development. To investigate whether these two genes are necessary for testis or ovary development, I generated conventional and conditional Irx3/5 double knockout mice. Interestingly, the absence of Irx3/5 during the early stage (~E13.5) did not have any effect on ovary and/or testis development but resulted in a loss of germ cells and a partial disruption of granulosa cell formation in postnatal day 0 (P0) stage. However, there were no difficulties in testis development.In summary, this thesis presents evidence that the Ft locus plays a critical role during embryonic and postnatal ovarian and testis development. In addition, we present evidence to propose that the proper expression patterns of six genes within the Ft locus are necessary for normal ovarian and testis development through maintaining communication between somatic and germ cells.