| dc.description.abstract | Autism spectrum disorder (ASD) describes a range of neurodevelopmental disorders characterised by impaired social interaction, delayed language development and repetitive or restrictive behaviours. JAKMIP1 was initially identified as an ASD candidate gene due to its dysregulated expression in syndromic forms of ASD, suggesting potential involvement in convergent cellular pathways relevant to ASD aetiology. Additionally, Jakmip1-deficient mice are reported to exhibit core ASD-associated behaviours. Yet, the molecular functions of JAKMIP1, and how its dysregulation leads to ASD-associated behaviours, remain unclear.
JAKMIP1 possesses multiple functional domains. Its C-terminus interacts with Janus Kinases (JAKs) that typically associate with cytokine receptors and trigger downstream Signal Transducer and Activator of Transcription (STAT) signalling following receptor activation. However, it is uncertain whether JAKMIP1 participates in neuronal cytokine/JAK/STAT signalling as the functional consequence of JAKMIP1-JAK interactions has not been explored.
Using JAKMIP1-knockout human neuroblastoma SH-SY5Y cells generated by CRISPR-Cas9 technology, I discover a novel role for JAKMIP1 in modulating IL-6/JAK1/STAT3 signalling through transcriptional regulation of STAT3 expression. JAKMIP1-deficient SH-SY5Y cells show impaired responses to IL-6, characterised by reduced IL-6-induced STAT3 activity and neurite outgrowth. Supporting this, transcriptional profiling revealed that JAKMIP1 may regulate the expression of various cytokine signalling-related genes, some directly encoding IL-6/JAK1/STAT3 pathway components.
In addition to cytokine signalling, various genes involved in neuronal migration, axon guidance and synaptogenesis were differentially expressed in JAKMIP1-knockout SH-SY5Y cells. Gene set over-representation analyses also indicate that ASD-associated genes are disproportionately affect by JAKMIP1 deficiency and that a subset of JAKMIP1-regulated genes significantly overlap with genes differentially expressed in models of neurodevelopmental disorders.
Furthermore, I demonstrate that the JAKMIP1 C-terminus can modulate STAT3 expression, likely via a nuclear mechanism, and use proteomic techniques to characterise the JAKMIP1 interactome. Remarkably, JAKMIP1 interacts with a multitude of RNA-binding proteins that control various aspects of mRNA synthesis and processing, many of which are implicated in neurodevelopmental disorders. This hints towards further areas for convergence among JAKMIP1-regulated genes and protein interactions in ASD-related pathways.
Altogether, this thesis presents evidence that identifies JAKMIP1 as a novel modulator of neuronal cytokine signalling through gene expression regulation. As neuroinflammatory signalling abnormalities are strongly associated with ASD, further investigation into the neurodevelopmental role of JAKMIP1-modulated IL-6/STAT3 signalling and the consequences of its dysregulation in ASD are clearly warranted. | en_GB |
