Bsx, short for Brain-specific homeobox, is a highly conserved homeodomain transcription factor. It plays crucial roles in multiple biological processes, including the development of the pineal complex and the differentiation of neuromodulatory cell populations in the secondary prosencephalon. It is involved in pathways related to circadian rhythms, appetite regulation, and the biosynthesis of melatonin [1,2,3]. Genetic models, such as gene knockout in zebrafish, are valuable for studying its functions.

In zebrafish, bsx loss-of-function mutations lead to significant phenotypes. Embryos fail to form a parapineal organ and develop right-isomerized habenulae. Key enzymes in the melatonin biosynthesis pathway are not expressed, and genes involved in phototransduction are abnormally expressed, indicating its pivotal role in pineal complex cell differentiation [1]. In adult zebrafish, bsx-/-mutants show a lack of a detectable pineal gland structure, pigmentation changes in the pineal window, and greatly reduced pineal transcripts. Larval locomotor activity analysis reveals altered circadian rhythmicity with reduced amplitudes [4]. In addition, in zebrafish, Bsx is necessary for the expression of many neuropeptide-encoding genes in distinct hypothalamic anatomical domains, and is critical for the development of serotonergic, histaminergic, and nitrergic neurons in the hypothalamus [2]. In goldfish, fasting increases BSX expression in the hypothalamus and telencephalon, suggesting its role in appetite regulation [3].

In conclusion, Bsx is essential for the development of the pineal complex, the regulation of circadian behavior, and the differentiation of multiple neuromodulatory cell types in the forebrain. The gene knockout models in zebrafish have provided valuable insights into these functions, and further research may help understand its potential implications in related physiological and pathological conditions, especially those related to circadian rhythm disorders and appetite-related diseases.