# Neurotrophic Modulation Restores Motor and Developmental Defects in Zebrafish Models of ints11 Deficiency

## TL;DR

This study uses zebrafish to model INTS11 deficiency and shows that neurotrophic treatments can restore motor and developmental defects linked to this genetic disorder.

## Contribution

The first in vivo zebrafish model of INTS11-associated neurodevelopmental dysfunction is established, revealing conserved mechanisms and potential therapeutic strategies.

## Key findings

- ints11 deficiency in zebrafish causes motor and behavioral deficits similar to human patients.
- Pharmacological treatments like BDNF and OligoGM1 rescue the observed neurodevelopmental defects.
- ints11 loss leads to dysregulated gene expression affecting neuronal and glial maturation.

## 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.

The study investigates the functional consequences of INTS11 loss‐of‐function (LoF), a genetic alteration linked to neurodevelopmental disorder (NDD), using zebrafish as an in vivo model. To model ints11 deficiency, two complementary approaches are applied: morpholino‐mediated knock‐down and CRISPR–Cas9 transient knock‐out, establishing ints11‐LoF conditions for phenotypic analysis. Behavioral assays reveal abnormal sensorimotor responses to visual and tactile stimuli, consistent with impaired nervous system function. At the cellular level, ints11 disruption leads to altered neural differentiation, with an expansion of neural precursor populations and a reduction of glial lineages, including oligodendrocytes and astrocytes. Injection of ints11 mRNA rescues the observed defects, demonstrating that the phenotype is specifically driven by ints11 loss‐of‐function rather than off‐target or procedural effects. Moreover, the improvement following pharmacological treatment (e.g., BDNF and OligoGM1) indicates that ints11‐dependent neurodevelopmental alterations can be at least partially mitigated pharmacologically, supporting the feasibility of therapeutic intervention for INTS11‐associated pathology. Overall, the findings support a key role for ints11 in regulating neurodevelopmental and indicate that ints11‐LoF in zebrafish recapitulates NDD‐relevant mutated‐patients phenotypes.