Biology subjects

Garcia-Forn, M.

Publications and source records attributed to Garcia-Forn, M..

3 recordsLinked to original sources

bioRxiv2024

Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X

DDX3X is an X-linked RNA helicases that escapes X chromosome inactivation and is expressed at higher levels in female brains. Mutations in DDX3X are associated with intellectual disability (ID) and autism spectrum disorder (ASD) and are predominantly identified in females. Using cellular and mouse models, we show that Ddx3x mediates sexual dimorphisms in brain development at a molecular, cellular, and behavioral level. During cortical neuronal development, Ddx3x sustains a female-biased signature of enhanced ribosomal biogenesis and mRNA translation. Female neurons display higher levels of ribosomal proteins and larger nucleoli, and these sex dimorphisms are obliterated by Ddx3x loss. Ddx3x regulates dendritic outgrowth in a sex- and dose-dependent manner in both female and male neurons, and dendritic spine development only in female neurons. Further, ablating Ddx3x conditionally in forebrain neurons is sufficient to yield sex-specific changes in developmental outcomes and motor function. Together, these findings pose Ddx3x as a mediator of sexual differentiation during neurodevelopment and open new avenues to understand sex differences in health and disease.

neuroscience↗

bioRxiv2021

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

BackgroundMutations in the X-linked gene DDX3X account for ~2% of intellectual disability in females, often co-morbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/-) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. ResultsDdx3x+/- mice show physical, sensory, and motor delays that evolve into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments, and motor deficits. Motor function further declines with age. These behavioral changes are associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning is accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. ConclusionsThese data shed new light on the developmental mechanisms driving DDX3X syndrome and support face validity of this novel pre-clinical mouse model.

neuroscience↗

bioRxiv2020

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington's disease

Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing an involvement of increased lamin B1 levels in the pathophysiology of Huntingtons disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging we demonstrate that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, which could contribute to transcriptional alterations we determined by RNA sequencing. Supporting lamin B1 alterations as a causal role in mutant-huntingtin mediated neurodegeneration, pharmacological normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work point out increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.

neuroscience↗