Abstract
Neurodevelopmental disorders (NDD) are a group of disorders that include intellectual disability. Although several genes have been implicated in NDD, the molecular mechanisms underlying its pathogenesis remain unclear. Therefore, it is important to develop novel models to analyze the functions of NDD-causing genes in vivo. Recently, rare pathogenic variants of the B-cell lymphoma/leukemia11A/B (BCL11A/B) gene have been identified in several patients with NDD. Drosophila carries the Chronophage (Cph) gene, which has been predicted to be a homolog of BCL11A/B based on the conservation of the amino acid sequence. In the present study, we investigated whether nervous system-specific knockdown of Cph mimics NDD phenotypes in Drosophila. Nervous system-specific knockdown of Cph induced learning and locomotor defects in larvae and epilepsy-like behaviors in adults. The number of synaptic branches was also elevated in the larval neuromuscular junction without a corresponding increase in the number of boutons. Furthermore, the expression levels of putative target genes that are Drosophila homologs of the mammalian BCL11 target genes were decreased in Cph knockdown flies. These results suggest that Cph knockdown flies are a promising model for investigating the pathology of NDD-induced BCL11A/B dysfunction.
Overview
- The study investigates the role of the Chronophage (Cph) gene in neurodevelopmental disorders (NDD) by using Drosophila as a model organism. The hypothesis being tested is whether nervous system-specific knockdown of Cph can mimic NDD phenotypes in Drosophila. The methodology used for the experiment includes nervous system-specific knockdown of Cph in larvae and adults, and the analysis of learning and locomotor defects, epilepsy-like behaviors, synaptic branching, and expression levels of putative target genes. The primary objective of the study is to investigate the pathology of NDD-induced BCL11A/B dysfunction using Cph knockdown flies as a model.
Comparative Analysis & Findings
- The study found that nervous system-specific knockdown of Cph induced learning and locomotor defects in larvae and epilepsy-like behaviors in adults. The number of synaptic branches was also elevated in the larval neuromuscular junction without a corresponding increase in the number of boutons. Furthermore, the expression levels of putative target genes that are Drosophila homologs of the mammalian BCL11 target genes were decreased in Cph knockdown flies. These results suggest that Cph knockdown flies are a promising model for investigating the pathology of NDD-induced BCL11A/B dysfunction.
Implications and Future Directions
- The study's findings suggest that Cph knockdown flies can be used as a model for investigating the pathology of NDD-induced BCL11A/B dysfunction. Future research directions could include further investigation of the molecular mechanisms underlying the effects of Cph knockdown on NDD phenotypes, as well as the use of Cph knockdown flies to test the efficacy of potential treatments for NDD. Limitations of the study include the use of a single model organism and the need for further validation of the findings in other species.