7251 Heterozygous Sox2 Knockout Mice have Delayed Puberty, Fertility Deficiencies, and a Decreased Number of GnRH Neurons

Abstract Disclosure: J. Cassin: None. R.D. Nguyen: None. K.J. Tonsfeldt: None. G.A. Dunn: None. V. Chen: None. S.E. Yeo: None. P.L. Mellon: None. Mutations in the SOX2 gene have been previously linked to a syndromic form of Isolated Hypogonadotropic Hypogonadism (IHH), with additional ocular and neurodevelopmental phenotypes. Recently, we published research detailing novel variants in SOX2, which demonstrated a functional role for SOX2 in Kisspeptin-expressing hypothalamic neurons, establishing a mechanistic relationship between SOX2 heterozygous variants and IHH. To further test the role of SOX2 in the hypothalamus, we utilized Sox2tm[1].[1]Lan/J mice to generate whole body heterozygous knockout (Sox2het) mice. We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2het mice compared to wild type (WT) controls (male WT: 29.7±0.7 days, Sox2het: 32.3±0.5 days and female WT: 28.8±0.9 days, Sox2het: 33.8±1 days). This difference is explained in part by a weight phenotype with Sox2het mice being significantly smaller at weaning and into adulthood despite observing no difference in weight at birth. We next examined the effect of Sox2het on fertility in both sexes. Sox2het male mice had a significant decrease in sperm motility compared to WT controls (WT: 40.4%±1.5, Sox2het: 29.5%±1.3); however, this decrease was insufficient to affect time to first litter or to decrease the number of pups per litter. In females, we observed a significant delay in time to first litter of Sox2het dams compared to WT controls (WT: 20.6±0.4 days, Sox2het: 26.5±1.7 days), which may arise from disrupted estrous cyclicity. Although Sox2het females did not spend an extended period of time in any one stage, they did not progress linearly through the stages as did their WT controls and therefore completed fewer cycles during our study (WT: 3.6±0.3 cycles, Sox2het: 2.5±0.2 cycles in 21 days). Finally, we assessed the number of GnRH neurons in the adult mouse and found that Sox2het mice have significantly fewer GnRH neurons (WT: 570.6±42.8 neurons, Sox2het: 228.4±32.8 neurons). Together these data further substantiate a role for SOX2 in the HPG axis by addressing the effects of Sox2 heterozygous knockout on the hypothalamus. Future studies will further define the role of SOX2 directly in the Kisspeptin and GnRH neurons. Presentation: 6/3/2024