The microtubule-associated protein astrin transgenesis rescues spermatogenesis and renal function in hypogonadic...

Male hypogonadic (hgn/hgn) rats show male sterility, reduced female fertility, progressive renal insufficiency and body growth retardation. These defects are associated with loss-of-function mutation of astrin and appear to be related to organ hypoplasia resulting from abnormal cell proliferation and increased cell death during embryonic and early postnatal development. As targeted disruption of mouse spag5 (astrin ortholog) has been reported to show no phenotype, we performed rescue experiments based on the introduction of rat astrin cDNA transgene into hgn/hgn rats to determine whether astrin is actually necessary for the establishment of normal male fertility and renal function. Astrin transgenic (Tg) rats were mated with hgn/+ rats of the HGN strain, and Tg-hgn/+ rats were then crossed to obtain Tg-hgn/hgn. Tg-hgn/hgn males showed recovery of body growth, fertility and renal function. Testis size was smaller in these transgenic animals than normal controls, but showed an increase by 16.5-fold compared with hgn/hgn males. Spermatogenesis occurred in Tg-hgn/hgn testes, and their accessory reproductive organs were of approximately normal size. hgn/hgn males show hypergonadotropic hypogonadism. Increased testosterone and decreased LH levels in Tg-hgn/hgn serum indicated the recovery of Leydig cells' function. Tg-hgn/hgn males showed normal reproductive behaviour, and their mating with Tg-hgn/hgn females produced pups in normal litter size. Their renal sizes and glomerular numbers showed complete recovery, and renal function assayed by biochemical parameters was normal. These results indicated that the transgene is functional in the testis and kidney development as well as body growth. In conclusion, astrin is necessary for the establishment of normal size (cell number) and function of the testis and kidney in rats.