Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

Abstract

Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub‐family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co‐ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

Neuronal LRP4 directs the development, maturation and cytoskeletal organization of Drosophila peripheral synapses

“…SR-protein specific kinases (SRPKs) were initially discovered to phosphorylate SR proteins and promote the subsequent nuclear import of mRNA splicing factors ( Zhou and Fu, 2013 ). More recent work, however, has demonstrated numerous roles in neuronal development and disease ( Bustos et al, 2020 ; Chan and Ye, 2013 ; Giannakouros et al, 2011 ; Hogg and Findlay, 2023 ). One Drosophila SRPK homologue, SRPK79D, has emerged as an important player in NMJ active zone biology ( Driller et al, 2019 ; Johnson et al, 2009 ; Nieratschker et al, 2009 ).…”

Neuronal LRP4 directs the development, maturation, and cytoskeletal organization of peripheral synapses

“…SRPK79D functions with LRP4 to instruct development SR-protein specific kinases (SRPKs) were initially discovered to phosphorylate SR-proteins and promote the subsequent nuclear import of mRNA splicing factors (Zhou & Fu, 2013). More recent work, however, has demonstrated numerous roles in the nervous system, including in development and disease (Bustos et al, 2020;Chan & Ye, 2013;Giannakouros et al, 2011;Hogg & Findlay, 2023). One Drosophila SRPK homologue, SRPK79D, has emerged as an important player in active zone assembly at the NMJ (Johnson et al, 2009;Nieratschker et al, 2009).…”