FIGURE 2 | DYRK1A in normal brain development and Down syndrome.

From the following article:

Down syndrome: the brain in trisomic mode

Mara Dierssen

Nature Reviews Neuroscience 13, 844-858 (December 2012)

doi:10.1038/nrn3314

Down syndrome: the brain in trisomic mode

a | During mammalian brain development, the proper numbers of neurons must first be generated and specified to the correct cell type; they must then migrate to their appropriate position, which is often millimetres to centimetres away from the site of origin. One of the genes that is triplicated in Down syndrome and in several mouse models, and which is now strongly implicated in dorsal telencephalic ventricular zone (VZ) proliferation, is DYRK1A (dual specificity tyrosine-phosphorylation-regulated kinase 1A). DYRK1A is transiently expressed (DYRK1A ON phase) in single neuronal precursors that are localized to the subventricular zone (SVZ) and divide to give rise to neuronal-committed progenitors or to neurons directly160. DYRK1A expression, which is presumably caused by neurogenic signals, promotes cell cycle exit by increasing cyclin-dependent kinase inhibitor p27 (also known as CDKN1B) expression and facilitates the generation of prospective neurons, which remain in a quiescent state while DYRK1A levels are high. The subsequent decay in DYRK1A levels (DYRK1A OFF phase), which is presumably caused by differentiating signals, allows the neurons to differentiate161. b | Several studies in Down syndrome fetal brains and in the Ts65Dn mouse have shown that premature differentiation of new neurons occurs and that this results in fewer new neurons and a reduction in the expansion of the maturing cortical layers. DYRK1A overexpression in wild-type mice, which is induced by in utero electroporation162, inhibits proliferation, depleting the proliferative pool and inducing precocious neuronal differentiation. These specific DYRK1A-induced mechanisms may disrupt the normal process of corticogenesis in Down syndrome160. CP, cortical plate.

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