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NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.

ABSTRACT: Autism spectrum disorders are neurodevelopmental conditions with diverse aetiologies, all characterized by common core symptoms such as impaired social skills and communication, as well as repetitive behaviour. Cell adhesion molecules, receptor tyrosine kinases and associated downstream signalling have been strongly implicated in both neurodevelopment and autism spectrum disorders. We found that downregulation of the cell adhesion molecule NEGR1 or the receptor tyrosine kinase fibroblast growth factor receptor 2 (FGFR2) similarly affects neuronal migration and spine density during mouse cortical development in vivo and results in impaired core behaviours related to autism spectrum disorders. Mechanistically, NEGR1 physically interacts with FGFR2 and modulates FGFR2-dependent extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signalling by decreasing FGFR2 degradation from the plasma membrane. Accordingly, FGFR2 overexpression rescues all defects due to Negr1 knockdown in vivo. Negr1 knockout mice present phenotypes similar to Negr1-downregulated animals. These data indicate that NEGR1 and FGFR2 cooperatively regulate cortical development and suggest a role for defective NEGR1-FGFR2 complex and convergent downstream ERK and AKT signalling in autism spectrum disorders.

SUBMITTER: Szczurkowska J

PROVIDER: S-EPMC6113639 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.

Szczurkowska Joanna J Pischedda Francesca F Pinto Bruno B Managò Francesca F Haas Carola A CA Summa Maria M Bertorelli Rosalia R Papaleo Francesco F Schäfer Michael K MK Piccoli Giovanni G Cancedda Laura L

Brain : a journal of neurology 20180901 9

Autism spectrum disorders are neurodevelopmental conditions with diverse aetiologies, all characterized by common core symptoms such as impaired social skills and communication, as well as repetitive behaviour. Cell adhesion molecules, receptor tyrosine kinases and associated downstream signalling have been strongly implicated in both neurodevelopment and autism spectrum disorders. We found that downregulation of the cell adhesion molecule NEGR1 or the receptor tyrosine kinase fibroblast growth ...[more]

PMID: 30059965

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Project description:Studies of head size and brain volume in autism spectrum disorders have suggested that early cortical overgrowth may be followed by prematurely arrested growth. However, the few investigations quantifying cortical thickness have yielded inconsistent results, probably due to variable ages and/or small sample sizes. We assessed differences in cortical thickness between high-functioning adolescent and young adult males with autism spectrum disorders (n = 41) and matched typically developing males (n = 40). We hypothesized thinner cortex, particularly in frontal, parietal and temporal regions, for individuals with autism spectrum disorders in comparison with typically developing controls. Furthermore, we expected to find an age × diagnosis interaction: with increasing age, more pronounced cortical thinning would be observed in autism spectrum disorders than typically developing participants. T(1)-weighted magnetization prepared rapid gradient echo 3 T magnetic resonance imaging scans were acquired from high-functioning males with autism spectrum disorders and from typically developing males matched group-wise on age (range 12-24 years), intelligence quotient (≥ 85) and handedness. Both gyral-level and vertex-based analyses revealed significantly thinner cortex in the autism spectrum disorders group that was located predominantly in left temporal and parietal regions (i.e. the superior temporal sulcus, inferior temporal, postcentral/superior parietal and supramarginal gyri). These findings remained largely unchanged after controlling for intelligence quotient and after accounting for psychotropic medication usage and comorbid psychopathology. Furthermore, a significant age × diagnosis interaction was found in the left fusiform/inferior temporal cortex: participants with autism spectrum disorders had thinner cortex in this region with increasing age to a greater degree than did typically developing participants. Follow-up within group comparisons revealed significant age-related thinning in the autism spectrum disorders group but not in the typically developing group. Both thinner temporal and parietal cortices during adolescence and young adulthood and discrepantly accelerated age-related cortical thinning in autism spectrum disorders suggest that a second period of abnormal cortical growth (i.e. greater thinning) may be characteristic of these disorders.

Project description:BackgroundChallenging behaviours are highly prevalent in children and adolescents with autism spectrum disorders (ASD), but little is known about the prevalence and course of these behaviours during adulthood. The aims of this study were to describe the topography of challenging behaviours in a cohort of 106 young adults with ASD and to identify the risk factors for challenging behaviours. Our secondary objective was to study the changes in challenging behaviours from adolescence to early adult years.MethodThe present study uses data from the EpiTED prospective follow-up study in France. The presence of challenging behaviours was assessed by the Aberrant Behaviour Checklist (ABC) completed by parent informants. Several dimensions of behaviour were studied: irritability, stereotypy, lethargy, hyperactivity and self-injury. Clinical variables were collected on ASD symptom severity, cognitive and language levels, adaptive behaviours and comorbid medical disorders.ResultsThe presence of challenging behaviours at early adulthood was related to the young adult's cognitive and language level, ASD symptom severity and comorbid gastrointestinal and sleep disorders. The main risk factor for challenging behaviours was ASD symptom severity. The level of language impairment was a significant predictor of self-injury. Gastrointestinal disorders were a significant predictor of stereotypy. The change in behaviour topography from adolescence to early adult years corresponded with decreased parent report of hyperactivity, but no significant decrease in parent reports of irritability, stereotypy, lethargy and self-injurious behaviours.ConclusionsThe challenging behaviours in individuals with ASD persist in early adulthood and are related to core symptom severity, levels of cognitive and language impairments and medical comorbidity. The results emphasise the importance of early interventions for children with ASD to target cognitive and language abilities and to alleviate the severity of ASD symptoms. They also underscore the need to enhance opportunities for individuals with ASD to better communicate discomforts and pain in the context of medical illness.

Dataset Information

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.

Publications

NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.

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