Transcription Factor Pet-1/FEV as a Potential Therapeutic Target in Anxiety and Depressive Disorders

Serotonergic dysfunction contributes to anxiety and depressive disorders not only through altered neurotransmission but also via disruptions in developmental programming, circuit integration, stress responsivity, and neuroplasticity. The ETS-domain transcription factor Pet- 1 (human ortholog FEV) regulates serotonergic lineage specification and long-term neuronal maintenance, placing it at the core of serotonergic system organization. This review summarizes recent molecular, developmental, behavioral, circuit-level, and translational findings on Pet-1/FEV.

Peer-reviewed studies were identified through PubMed and Web of Science using combinations of the keywords "Pet-1", "FEV", "serotonergic neurons", and "mood disorders. Studies based on Pet-1/FEV function, serotonergic lineage specification, stress responsivity, circuit modulation, and human genetic or transcriptomic evidence were included.

Pet-1 deficiency reduces serotonergic neuron number, impairs serotonin-related gene expression, and disrupts limbic-prefrontal circuit connectivity. These alterations are associated with increased anxiety- and depression-like behaviors in both germline and adult conditional knockout models. Human studies further demonstrate selective FEV expression in raphe neurons and associations with amygdala reactivity and stress sensitivity, supporting translational relevance.

Loss of Pet-1 disrupts the serotonergic transcriptional program and alters raphe neuron activity, thereby destabilizing cortico-limbic circuit function and emotional regulation. Convergent evidence from animal and human studies indicates that Pet-1/FEV represents a critical regulatory node underlying vulnerability to anxiety and depressive disorders and a potential therapeutic target.

Pet-1/FEV represents a central regulator of serotonergic identity and affective behavior, although its translational applicability requires further validation in large-scale human studies and circuit-level studies.