Exploring the functions of JAKMIP1 in neuronal IL-6/STAT3 signaling and its relevance to chromosome 15q-duplication syndrome

Martin, J. G.; Martin, E.-R.; Takamura, N.; Harlow, C. E.; Bamford, R. A.; Smith, R. G.; Morgan, N. G.; Inaba-Inoue, S.; Mill, J.; Srivastava, D. P.; Dawe, H. R.; Chilton, J. K.; Russell, M. A.; Oguro-Ando, A.

doi:10.1101/2025.10.21.683757

bioRxiv · 10.1101/2025.10.21.683757

Exploring the functions of JAKMIP1 in neuronal IL-6/STAT3 signaling and its relevance to chromosome 15q-duplication syndrome

Martin, J. G.·Martin, E.-R.·Takamura, N.·Harlow, C. E.·Bamford, R. A.·Smith, R. G.·Morgan, N. G.·Inaba-Inoue, S.·Mill, J.·Srivastava, D. P.·Dawe, H. R.·Chilton, J. K.·Russell, M. A.·Oguro-Ando, A.

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Abstract

Growing evidence supports neuroinflammation as a risk factor for neurodevelopmental and psychiatric disorders. Interleukin 6 (IL-6), a classical pro-inflammatory cytokine, has been associated with autism spectrum disorder (ASD)-related phenotypes. To better understand molecular factors that modify neuronal cytokine responses in ASD, we investigated potential roles for JAKMIP1, a gene linked to chromosome 15q-duplication syndrome (Dup15q; a form of syndromic ASD), in regulating IL-6/STAT3 signaling. We observe that JAKMIP1 deficiency impairs IL-6/STAT3 signaling and IL-6-induced neuritogenesis in SH-SY5Y cells; and discover that JAKMIP1 may regulate STAT3 expression via its C-terminus, which exhibits nucleoplasmic localization. Additionally, we find that IL-6/STAT3 signaling is altered in Dup15q hiPSCs-derived cortical neurons, which display heightened responsiveness to IL-6; though it is unclear whether and how JAKMIP1 contributes to this. Overall, our findings identify JAKMIP1 as a modulator of neuronal IL-6/STAT3 signaling and support that ASD-linked genetic variants can alter the inflammatory landscape of ASD.

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Martin, J. G., Martin, E.-R., Takamura, N., Harlow, C. E., Bamford, R. A., Smith, R. G., Morgan, N. G., Inaba-Inoue, S., Mill, J., Srivastava, D. P., Dawe, H. R., Chilton, J. K., Russell, M. A., Oguro-Ando, A.. 2025-10-22. Exploring the functions of JAKMIP1 in neuronal IL-6/STAT3 signaling and its relevance to chromosome 15q-duplication syndrome. https://doi.org/10.1101/2025.10.21.683757

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