Current trends of high-risk gene Cul3 in neurodevelopmental disorders

Cul3 encodes Cullin-3, a core component of the ubiquitin E3 ligase that is involved in protein ubiquitination. Recent studies have identified Cul3 as a high-confidence risk gene in neurodevelopmental disorders (NDDs), especially autism spectrum disorder (ASD). Different strategies have been used to generate animal models with Cul3 deficiency in the central nervous system, including whole-brain knockout (KO), cell-type specific conditional KO (cKO), and brain region-specific knockdown. In this review, we revisited the basic properties of CUL3 and its function under physiological and pathological conditions. Recent clinical studies including case reports and large cohort sequencing studies related to CUl3 in NDDs have been summarized. Moreover, we characterized the behavioral, electrophysiological, and molecular changes in newly developed Cul3 deficiency models. This would guide further studies related to Cul3 in CNS and provide potential therapeutic targets for Cul3-deficiency-induced NDDs, including ASD.