Abstract
The formation of the functional mammalian cerebral cortex requires a concerted control of neurogenesis, neuronal migration, and neuronal morphogenesis. However, molecular mechanisms that control these processes are not well understood. We have found that the BMP signaling downstream transcription factor SMAD1 and CRMP2 (collapsin response mediator protein-2) are inversely and complementarily expressed in the developing neocortex. BMPs can suppress CRMP2 expression in cortical cells. Our ChIP assay demonstrates that both SMAD1 and -4 bind to CRMP2 promoter in the neocortex, and overexpression of SMAD1 and 4 in vivo suppresses CRMP2 expression. RNA interference of CRMP2 and overexpression of dominant negative forms of CRMP2 in utero cause accumulation of multipolar cells in the ventricular, subventricular, and intermediate zones and suppresses neurite outgrowth, suggesting that CRMP2 is required for multipolar to bipolar transition for directional neuronal migration and neurite outgrowth. Thus, our study reveals a novel mechanism that the BMP-SMAD signaling pathway controls neuronal migration and neurite outgrowth by suppressing the transcription of CRMP2.
Highlights
Subventricular zone (SVZ)3 and lower intermediate zone (IZ), which is known as the premigratory zone, and change to bipolar to migrating out of the premigratory zone along radial fibers to the cortical plate (CP), where they further become mature neurons [1,2,3,4,5]
Because overexpression of dominant negative (DN) forms of CRMP2 and knockdown of CRMP2 expression with different CRMP2 shRNAs led to the accumulation of cells in the VZ/subventricular zone (SVZ)/IZ, we looked at their morphology in detail in the SVZ and lower IZ to understand the role of CRMP2 in radial migration
We have demonstrated that the BMP-SMAD signaling pathway regulates the transcription and expression of CRMP2 during brain development both in vitro and in vivo
Summary
Subventricular zone (SVZ)3 and lower intermediate zone (IZ), which is known as the premigratory zone, and change to bipolar to migrating out of the premigratory zone along radial fibers to the cortical plate (CP), where they further become mature neurons [1,2,3,4,5]. To determine whether SMAD1 and -4 play a role in regulating the expression of CRMP2 in the cerebral cortex, we performed ChIP assays in both E16 rat cerebral cortex and E14 mouse cerebral cortex and found that both SMAD1 and -4 bind to the CRMP2 promoter region in both rat and mouse cortical cells (Fig. 3A and supplemental Fig. S2).
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