ABSTRACT Introduction Gli2 +/− , Gli3 +/𝛥699 , and Gli2 +/− ; Gli3 +/𝛥699 mutant mice, novel models for variations in sex characteristics (VSCs), were used to investigate the impact of GLI2 and GLI3 modulation on the relationship between the development of anxiety‐like behavior, social behavior, and peripheral morphology. Aim Uncover how altered GLI profiles modulate urogenital, neuroendocrine, and behavioral systems. Hypothesis Increased disruption of the GLI2/GLI3 regulatory axis will display increases in the severity of urogenital dysmorphogenesis and concurrent alterations in juvenile social and anxiety‐like behaviors. Methods Male and female mice were tested in social interaction and open field testing at postnatal days (PNDs) 24–26 and 26–29, respectively. Following behavioral testing, anogenital distance (AGD), plasma steroids: testosterone and corticosterone, and the volume of the sexually dimorphic nucleus (SDN) were taken and analyzed. Results Significant differences in social and anxiety‐like behaviors among genotypes were documented. Female double heterozygote Gli2 +/− ; Gli3 +/𝛥699 mice showed reduced social behavior and increased anxiety‐like behaviors. Gli2 +/− mice exhibited sex‐specific changes in anxiety‐like behaviors. Conversely, no behavioral differences were observed in Gli3 +/𝛥699 mice. Gli2 +/− mice and female Gli2 +/− ; Gli3 +/𝛥699 mice showed reduced AGD. No genotypic variations were observed in SDN volume or plasma steroids. Conclusion These data suggest that morphogens that are involved in peripheral variations in sexual characteristics may also be involved in regulating anxiety‐like and social development. This not only underscores the importance of mouse models in understanding genital variations and their relationship to juvenile behavior but also may be used to inform clinical approaches to those with VSCs with increased mental health concerns.
Niepsuj et al. (2026) studied this question.