ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neuropathology
Neuronal differentiation and activity drive nucleocytoplasmic shuttling of the intellectual disability kinase TLK2
Provisionally accepted
- Department of Biology and York Biodmedical Research Institute, University of York, York, United Kingdom
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Autosomal dominant intellectual developmental disorder 57 (MRD57) is a rare neurodevelopmental disorder characterised by delayed language and psychomotor development, intellectual disability, hypotonia, gastrointestinal issues and facial dysmorphia. It is linked to genetic mutations in the serine/threonine kinase TLK2, characterised by haploinsufficiency and in some cases, its loss or impaired kinase function. TLK2 is an established cell cycle regulator that has been extensively studied in mitotic cells. It is upregulated in cancers, driving tumour growth, however, the role of TLK2 in postmitotic neurons is not understood. We therefore aimed to gain insight into how TLK2 mutations cause MRD57 by determining where TLK2 is expressed in the brain and its subcellular localisation during neuronal differentiation. Public human and mouse brain transcriptomic data revealed splice variant diversity in the N-terminus of TLK2, which contains its nuclear localisation sequence (NLS). Using splice-specific in situ hybridisation probes, we observed expression of TLK2 transcripts that contain and lack the NLS in the mouse hippocampus and cerebellum. Surprisingly, immunohistochemistry revealed TLK2 is predominantly cytoplasmic in the adult mouse brain. We followed up these findings in human SH-SY5Y neuroblastoma cells, and found that neuronal differentiation enhances a cytoplasmic pool of TLK2 by two mechanisms: nuclear export of full length TLK2 and increased expression of TLK2 splice variants lacking the NLS. Finally, acute stimuli that mimic synaptic activity were sufficient to elicit nuclear export of TLK2. Our data highlight the need to establish the neuronal cytoplasmic substrates of TLK2 and determine how the loss of TLK2 activity in MRD57 might impact their function in the developing and mature brain.
Keywords: kinase, neurodevelopmental disorder, neuronal differentiation, Nuclear localisation signal, splice variant
Received: 05 Sep 2025; Accepted: 22 Dec 2025.
Copyright: © 2025 Nuhu-Soso, Denton, Goffin, Hahn and Evans. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Gareth J.O. Evans
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