Antagonistic Effects of Doublecortin and MARK2/Par-1 in the Developing Cerebral Cortex

Abstract

Abnormal neuronal migration is manifested in brain malformations such as lissencephaly. The impairment in coordinated cell motility likely reflects a faulty mechanism of cell polarization or coupling between polarization and movement. Here we report on the relationship between the polarity kinase MARK2/Par-1 and its substrate, the well-known lissencephaly-associated gene doublecortin (DCX), during cortical radial migration. We have previously shown using in utero electroporation that reduced MARK2 levels resulted in multipolar neurons stalled at the intermediate zone border, similar to the phenotype observed in the case of DCX silencing. However, whereas reduced MARK2 stabilized microtubules, we show here that knock-down of DCX increased microtubule dynamics. This led to the hypothesis that simultaneous reduction may alleviate the phenotype. Coreduction of MARK2 and DCX resulted in a partial restoration of the normal neuronal migration phenotype in vivo. The kinetic behavior of the centrosomes reflected the different molecular mechanisms activated when either protein was reduced. In the case of reducing MARK2 processive motility of the centrosome was hindered, whereas when DCX was reduced, centrosomes moved quickly but bidirectionally. Our results stress the necessity for successful coupling between the polarity pathway and cytoplasmic dynein-dependent activities for proper neuronal migration.

Guiding Neuronal Cell Migrations

“…In particular, the centrosome-containing cytoplasmic swelling can move backward toward the nucleus in Dcx mutant neurons, indicating a problem in the polarization of organelles in these cells. Consistently, knockdown of Dcx in pyramidal cells leads to an abnormally hyperactive centrosome, with loss of directional movement and lack of spatial correlation with the nucleus (Sapir et al 2008). In addition, the centrosome-nucleus uncoupling observed in Lis1 or dynein-deficient cells is rescued by DCX expression (Tanaka et al 2004).…”

SAD kinases control the maturation of nerve terminals in the mammalian peripheral and central nervous systems

“…SADs are 2 members of a 12-member kinase subfamily, most of which are expressed in neurons. The MARK and NUAK members of the AMPK subfamily of kinases also influence neuronal polarity and axon branching, respectively (44,45), and thus may act in parallel with SADs in some circumstances. NUAKs also influence presynaptic mitochondrial dynamics during synapse development (45).…”

Neuronal polarization

“…Brsk1/Brsk2 double knockout neurons have a mixed axon/dendrite identity (Kishi et al, 2005;Barnes et al, 2007), and the developing cortex of Brsk1/Brsk2 double knockout mice shows a loss of axons and abnormally orientated dendrites (Kishi et al, 2005). In addition, the downregulation of MARK2 by shRNA also impairs the MP-to-BP transition (Sapir et al, 2008). The cAMP-dependent phosphorylation of LKB1 is also involved in GABA B receptor-induced axon/dendrite outgrowth and neuronal migration in vivo (Bony et al, 2013).…”