Control of Cortical Neuron Migration and Layering: Cell and Non Cell-Autonomous Effects of p35

Abstract

The migration, arrest, and ultimately positioning of cortical neurons require signaling activity from Reelin as well as from cyclindependent kinase 5 (Cdk5). Although both molecules control neuronal positioning, they achieve their effects by quite separate molecular pathways. Cdk5 is a serine-threonine kinase, the activity of which is dependent on its activating subunits p35 and p39. Mice deficient in Cdk5, p35, or both p35 and p39 display the hallmarks of disturbed cortical development, including cortical layer inversion, neuronal disorientation, and abnormal fiber infiltration. To distinguish between the cell-and non cell-autonomous functions of p35, we constructed p35Ϫ/Ϫ chimeras using the lacZ gene as an independent marker for p35 ϩ/ϩ cells. In this shared developmental space, wild-type and mutant neurons behaved cell-autonomously with respect to layering. Wild-type cells formed a properly layered supercortex that is mirrored by an inverted mutant cortex lying underneath. However, this genotype-specific behavior was confined to the pyramidal population, and interneurons belonging to either genotype were indiscriminately distributed. However, there was also non cell-autonomous rescue of mutant neurons, and this rescue was specific only to early-born pyramidal neurons belonging to layer V. Rescued neurons reached the correct layer address and possessed appropriate neuronal morphology, orientation, and projections. Later-born neurons belonging to layers II and III were not rescued. These results demonstrate that p35 signaling can have both cell-and non cell-autonomous consequences, and their effects are not uniformly shared by cortical neurons born at different times or born at different places (projection neurons vs interneurons).

Layer Positioning of Late-Born Cortical Interneurons Is Dependent on Reelin But Not p35 Signaling

“…Clearly, late-born interneuron positioning in p35 mutants is unaffected despite the inversion of all pyramidal neuron layers. This confirms previous observations in p35 chimeras wherein all interneurons appear to be randomly distributed despite genotype-specific segregation of pyramidal neurons (Hammond et al, 2004). Similar conclusions, that interneuron positioning is unaffected by the Cdk5/p35 pathway, has been suggested previously in chimeric studies using Cdk5 mutants (Gilmore and Herrup, 2001).…”

Cellular and molecular introduction to brain development

“…The interactions between these proteins and microtubules are largely regulated by posttranslational modification. In particular, the function of Dcx and kinesins appears to be regulated by phosphorylation by the Cdk5 kinase (Hammond et al, 2004; Nishimura et al, 2014). …”

Genetic Fate Mapping Reveals That the Caudal Ganglionic Eminence Produces a Large and Diverse Population of Superficial Cortical Interneurons

“…It has been shown that cortical interneurons, like pyramidal neurons (Angevine II and Sidman, 1961), are largely generated in an inside-out layering pattern within the neocortex (Fairen et al, 1986; Hammond et al, 2004; Miller, 1985; Rymar and Sadikot, 2007; Yozu et al, 2004). We have previously shown that this is also the case for MGE-derived interneurons (Miyoshi et al, 2007).…”