Cc2d1a, also known as Freud-1, belongs to a gene family with conserved domains including DM14, a helix-loop-helix domain, and a C2 calcium-dependent phospholipid binding domain. It functions as a transcriptional repressor of the serotonin-1A receptor gene and is involved in regulating multiple intracellular signaling pathways, with a particularly strong effect on the NF-κB pathway [4,8]. It is also associated with endosomal sorting pathways by interacting with CHMP4 family proteins, regulating degradation and signaling of transmembrane receptors like EGFR and TLR4 [7].

In KO/CKO mouse models, conditional deletion of Cc2d1a in glutamatergic neurons leads to autistic-like features such as self-injurious repetitive grooming, aberrant social interactions, decreased dendritic complexity, and increased synaptic excitation/inhibition ratio [2]. In male mice lacking Cc2d1a in forebrain excitatory neurons, there is increased irritability-like behavior, which is related to reduced oxytocin-expressing neurons in the hypothalamus [6]. Conditional deletion from excitatory neurons in male mouse forebrain also impairs hippocampal synaptic plasticity, cognitive function, and object location memory, and is associated with enhanced Rac1 activity [5]. Heterozygous Cc2d1a mice show sex-dependent autophagy impairment in the prefrontal cortex and hippocampus [3]. In Xenopus, loss of cc2d1a causes cardiac heterotaxy, cystic kidneys, and abnormal CSF circulation due to defective ciliogenesis [1].

In conclusion, Cc2d1a is crucial for normal brain development, ciliogenesis, and CSF circulation. Cc2d1a KO/CKO mouse models have revealed its roles in neurodevelopmental disorders such as autism spectrum disorder, intellectual disability, and related behavioral abnormalities, providing insights into the underlying mechanisms and potential therapeutic targets for these diseases.