Adkins, A.; Glowinski, K.; Kim, Y.-I.; Wright, E.; Bennett, C. E.; Nelson, J. C.; Sagerstrom, C. G.

Behavioral dysfunction is a common characteristic of many mental health disorders. While the causes of these disorders vary, aberrant behaviors may arise from alterations in transcriptional regulation already during early neural development. Because transcription factors (TFs) often belong to families of closely related members, disruption of a single TF may indirectly influence the functionality of other family members. Consequently, mutations in TFs within the same family may lead to overlapping, yet distinct, phenotypes. This feature of TF function has important implications for understanding behavioral phenotypes, but detailed analyses across a single TF family are still lacking. In this study, we present a comprehensive behavioral analysis of adult zebrafish harboring mutations in individual members of the TALE and Hox TF families, that are essential for nervous system development. Using a battery of validated behavioral assays, we uncover elevated stress responses among all TF mutant lines, as well as TF-specific dysregulation in coping strategies, social interaction, learning/memory, and endurance and locomotion. The shared behavioral abnormalities across mutants suggests TF family members converge on core developmental pathways for stress-related behavioral regulation, while mutation-specific phenotypes indicate unique roles for individual TFs in fine-tuning neural function. Our findings provide a systematic behavioral characterization of TALE and Hox mutants in a vertebrate model and provide a framework for understanding how genetic variation within TF families may differentially contribute to vulnerability for mental health disorders.