ROLE OF DYRK1A IN EARLY NEOCORTICAL DEVELOPMENT: IMPLICATIONS FOR INTELLECTUAL DISABILITY SYNDROMES

DYRK1A is a chromosome 21 dosage-dependent kinase essential for brain development. Triplication of the DYRK1A gene contributes to several neurological features of Down syndrome, whereas DYRK1A haploinsufficiency causes a syndromic form of intellectual disability associated with microcephaly. Using loss of-function (LoF) and gain-of-function (GoF) Dyrk1a mutant mouse models, we previously showed a direct correlation between brain growth and Dyrk1a gene dosage, which was associated with defects in corticogenesis.
Here, we investigated DYRK1A function at the apical end-foot of neural stem cells (NSCs), a domain essential for maintaining cell polarity, delamination, and ventricular surface growth. In the mouse embryonic neocortex, GoF Dyrk1a mutants showed increased apical domain size, whereas LoF mutants showed a reduction. Pharmacological inhibition of DYRK1A reduced apical domain size in the chick neural tube. Moreover, DYRK1A overexpression by in ovo electroporation expanded the apical domain, whereas kinase-dead DYRK1A had no effect.
Leucine Zipper Tumor Suppressor 1 (LZTS1), a putative DYRK1A interactor that promotes apical contraction and delamination, reduced apical domain size in chick NSCs. This phenotype was rescued by co-overexpression of DYRK1A, but not by the kinase-dead form. Furthermore, pull-down and in vitro kinase assays demonstrated that DYRK1A interacts with and phosphorylates LZTS1 at three serine residues in its N-terminal region.
Altogether, these data support a model in which DYRK1A activity restrains the contractile action of LZTS1 at the apical domain of NSCs, providing a mechanistic link between DYRK1A dosage, cortical expansion, and neurogenesis.