Emerging roles of the DLK1-DIO3 imprinted domain in neurodevelopment and complex neurological and psychiatric disorders

The DLK1-DIO3 genomic domain comprises a cluster of imprinted genes regulated by epigenetic mechanisms that precisely regulate their expression dosage, often in a timely and tissue-specific manner. This is particularly significant during brain development, as transcripts from the DLK1-DIO3 domain are involved in the physiology of most neural cell types, regulating fundamental processes such as neural precursor cell proliferation, neuronal and glial lineage specification, and subsequent functional maturation, as well as the establishment of neural and neuroendocrine circuits. Thus, disruption of the DLK1-DIO3 epigenome, induced not only by genetic alterations but also by neurodevelopmental exposure to environmental factors and maternal disease, may produce abnormal transcript expression within the domain, leading to broader dysregulation of brain gene expression programs during fetal and early development, ultimately influencing brain function and neurological and neuroendocrine phenotypes later in life. Here, we reviewed genetic, epigenetic, environmental, neurobiological, and behavioral studies linking dysregulation of genes within the DLK1-DIO3 imprinted domain to neurological and psychiatric outcomes, including autism spectrum disorder, schizophrenia, anxiety and depression, epilepsy, neurodegenerative disorders, susceptibility to drug abuse, maladaptive brain inflammatory response, and psychomotor alterations. Additional outcomes include neuroendocrine disorders and associated behavioral alterations. This narrative review covers the increasing observations in humans associating molecular signatures in this domain with neurological and psychiatric conditions, as well as studies in human induced pluripotent stem cell-derived neural cells and in rodents that provide compelling mechanistic insights about the neurodevelopmental processes affected, which could help interpret the unresolved etiology of these disorders, including increased prevalence, missing heritability, and phenotypical heterogeneity.