This is consistent 5-Fluoracil with the requirement of acetylated tubulin for migration and process

formation in neurons (Creppe et al., 2009 and Heng et al., 2010) and implies cell-type-specific effects of RhoA on the tubulin cytoskeleton in RG. Thus, the effect of RhoA deletion in the developing cerebral cortex causes a profound destabilization of the actin and tubulin cytoskeleton in RG resulting in a loss of apical anchoring and epithelial architecture, as well as defects in basal process formation or maintenance. Together with the results from transplanting WT cells into RhoA cKO cerebral cortices, which also settle either in the upper normotopic cortex or in the SBH, these data demonstrate that defects in RGs are sufficient to cause the phenotype of a double cortex. Thus, even WT neurons after transplantation often do not reach the pial surface and settle in the SBH, while a few of them reach the upper normotopic cortical plate position supposedly when ending up close to a radial glia still in contact with the pial surface. This phenotype obviously worsens during development of the Trametinib cerebral cortex with more and more radial glial fibers severely disorganized and formation of a progenitor layer separating the upper and lower cortex by E16. Eventually neurons born by progenitors in the lower part of this progenitor layer seem even cut off from

signaling pathways, resulting in reduced levels of phospho-cofilin and a predominantly tangential mode of migration as discussed previously and thereby explaining the progressive worsening of the phenotype and the predominant accumulation of late generated neurons in the lower cortex, the SBH. These data suggest that “double cortex” formation may result due to defects in RG rather than in the migrating neurons themselves. While the hypothesis that RG defects may contribute to disorders of PH, where misplaced neurons directly appose the ventricle, has been

raised (Feng et al., 2006 and Sarkisian et al., 2006), this has not been tested and dysfunctions of the RG are not considered to be the sole cause for these malformations. Similarly, the mechanistic basis for SBH, in which the ectopic neurons do not directly appose the ventricle but are embedded into WM structures, has been considered to be a functional buy Afatinib defect intrinsic to the migrating neurons themselves (Bielas et al., 2004, Guerrini and Parrini, 2010 and Ross and Walsh, 2001). Interestingly, pathways affected in SBH were largely linked to the MT components of the cytoskeleton, such as Lis1, Dcx, and α-tubulin, with the later requiring acetylation (Creppe et al., 2009, Gleeson et al., 1998, Keays et al., 2007 and Reiner et al., 1993), while PH is most often caused by loss-of-function mutations in the Filamin A gene (Guerrini and Parrini, 2010 and Robertson, 2004), which crosslinks actin into networks or stress fibers. Moreover, loss of MEKK4 in the mouse resulted in increased phosphorylation of Filamin A and a PH phenotype (Sarkisian et al.