ABSTRACT Mutations in INTS11 , the catalytic subunit of the Integrator complex essential for RNA processing and transcriptional termination, have been linked to neurodevelopmental disorders (NDDs), yet the underlying mechanisms remain poorly understood. To address this gap, we developed and characterized a novel ints11 loss‐of‐function zebrafish model using CRISPR/Cas9 and morpholino‐based approaches, which recapitulates key phenotypic traits observed in human patients, including motor and behavioral deficits. ints11 deficiency led to marked impairments in locomotor activity and visual motor response, consistent with the neurological manifestations reported in INTS11 ‐mutated patients. These behavioral abnormalities were paralleled by significant dysregulation of neurodevelopmental gene expression, including decreased expression of islet1 , map2 , gfap , and mag , and upregulation of the progenitor marker nestin , indicating defective neuronal differentiation and glial maturation. Interestingly, the observed phenotypes are rescued not only by mRNA‐mediated re‐expression of ints11 , but also through pharmacological administration with brain‐derived neurotrophic factor (BDNF) and the GM1 ganglioside‐derived oligosaccharide (OligoGM1). These findings highlight neurotrophic signaling as a potential compensatory axis counteracting RNA‐processing defects. In conclusion, our work establishes the first in vivo zebrafish model of INTS11‐associated neurodevelopmental dysfunction, uncovering conserved molecular mechanisms that link Integrator complex activity, neurotrophic support, and neuronal maturation and providing a valuable platform for dissecting disease mechanisms and evaluating therapeutic strategies targeting RNA processing pathways and neurotrophic support in NDDs. image
Pistocchi et al. (Sun,) studied this question.