Expression pattern and function of the autism-associated gene DIPK2B during macrophage development

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by social communication deficits and restrictive behaviors. Immune cell dysfunction has been implicated in ASD pathology, with innate immune cells such as macrophages and microglia playing a key role in neurodevelopment. Macrophages secrete trophic factors that support neuronal growth and synaptic plasticity, while microglia mediate synaptic pruning, neuronal circuit refinement, and neuron phagocytosis. ASD is also strongly influenced by genetic factors, with many ASD-related genes implicated in synaptic function and neuronal communication. Given the association between ASD and immune cell dysfunction, studying genes involved in hematopoietic and immune cell development may offer insights into the pathophysiology of this disorder. Divergent Protein Kinase Domain 2B (DIPK2B) has been identified as a candidate risk-factor gene for ASD. DIPK2B may play a role in hematopoiesis by regulating the development of immune cells such as macrophages and microglia, as previous research has shown that dipk2b-deficient zebrafish larvae exhibit reduced microglial populations. This study aimed to characterize DIPK2B gene and DIPK2B protein expression during hematopoietic differentiation of human induced pluripotent stem cells (hiPSCs) and throughout zebrafish development. We found that DIPK2B/DIPK2B expression peaks at critical stages of hematopoietic differentiation in both hiPSC cultures and zebrafish embryos. Moreover, dipk2b loss-of-function resulted in a reduced number of cells in the macrophage and microglial populations of zebrafish embryos, suggesting that dipk2b is vital for early myeloid cell differentiation. These results support a potential role for DIPK2B in ASD pathogenesis, particularly regarding immune cell dysregulation. In conclusion, our findings highlight the importance of DIPK2B in early hematopoiesis, namely in macrophage and microglia development. Given its role in immune cell differentiation, DIPK2B could serve as a genetic diagnostic marker for particular subtypes of ASD associated with immune dysfunction, contributing to a more refined diagnosis and paving the way for targeted therapeutic interventions.