Biology subjects

Suetterlin, P.

Publications and source records attributed to Suetterlin, P..

3 recordsLinked to original sources

bioRxiv2025

Assigning Targetable Molecular Pathways to Transdiagnostic Subgroups Across Autism and Related Neurodevelopmental Disorders

The heterogeneity of autism and related neurodevelopmental conditions has impeded accurate prognoses and treatment discovery. Using translational neuroimaging across 135 mouse models (3,515 mice) and two human MRI datasets (n = 1,234 and n = 1,015), we derived participant subgroups from shared neuroanatomical features. These subgroups did not distinguish autism, ADHD, or OCD diagnoses and only modestly differentiated cognitive and behavioural phenotypes. Instead, they mapped onto four molecular pathways: (1) synaptic function; (2) MAPK and Wnt signalling; (3) chromatin modification and cellular stress responses; and (4) broader chromatin, immune, and second-messenger signalling pathways. This framework bridges preclinical models and idiopathic human neurodevelopmental conditions, linking patients to biologically relevant molecular mechanisms.

neuroscience↗

bioRxiv2018

Non-monotonic regulation of gene expression, neural progenitor fate and brain growth by the chromatin remodeller CHD8

Heterozygous CHD8 mutations are associated with autism and macrocephaly with high penetrance in the human population. The reported mutations may have loss-of-function (haploinsufficient), hypomorphic or dominant negative effects on protein function. To determine the effects of reducing CHD8 protein function below haploinsufficient levels on brain development, we established a Chd8 allelic series in the mouse. Chd8 heterozygous mice exhibited relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. In comparison, mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia, and significantly altered expression of over 2000 genes. Autism-associated genes were downregulated and neural progenitor proliferation genes upregulated. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, affecting genes and pathways that largely overlapped with those dysregulated in the mild hypomorphs. By contrast, homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in the induction of p53 target genes, cell cycle exit, apoptosis and pronounced brain hypoplasia. Intriguingly, increased progenitor proliferation in hypomorphs was primarily restricted to TBR2+ intermediate progenitors, suggesting critical roles for CHD8 in regulating the expansion of this population. Given the importance of these progenitors in human cortical growth, this observation suggests that human brain development might be more sensitive to CHD8 deficiency than the mouse. We conclude that brain development is acutely sensitive to CHD8 dosage and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage can result in non-linear effects on gene transcription and brain growth.

neuroscience↗

bioRxiv2017

Distinctive Behavioural Anomalies, Structural Brain Phenotypes And Cortical Hyper-Connectivity In Chd8-Deficient Mice

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. To investigate how reduced Chd8 gene dosage may disrupt brain development and predispose individuals to ASD, we generated a Chd8 heterozygous mouse model. In line with clinical observations, we found that Chd8 heterozygous mice displayed subtle brain hyperplasia and hypertelorism, coupled with increased postnatal brain weight. Chd8 heterozygous mice displayed anomalous behaviours, but autism-like social deficits, repetitive and restricted behaviours were not present. Only minor gene expression changes were observed in the embryonic neocortex at E12.5, with more pronounced gene expression changes in postnatal cortex at P5. Differentially expressed genes showed highly significant enrichment for known autism candidates. Amongst the down-regulated transcripts, genes involved in cell adhesion and axon guidance were particularly prominent, implicating impaired connectivity as a potential mechanism underlying the ASD phenotype. To probe this further, we performed resting state functional fMRI and found increased synchronised activity in cortico-hippocampal and auditory-parietal networks, hinting at impaired sensory processing. Together, these data show that Chd8 heterozygous mice recapitulate key clinical features found in patients with CHD8 mutations and show a unique combination of behavioural phenotypes, which may be underpinned by a distinctive disruption of brain connectivity and sensory processing.

neuroscience↗