Abstract
ABSTRACTRetinoic acid (RA) is a diffusible molecule involved in early forebrain patterning. Its later production in the meninges by the retinaldehyde dehydrogenase RALDH2 coincides with the time of cortical neuron generation. A function of RA in this process has not been adressed directly as Raldh2−/− mouse mutants are embryonic lethal. Here, we used a conditional genetic strategy to inactivate Raldh2 just prior to onset of its expression in the developing meninges. This inactivation does not affect the formation of the cortical progenitor populations, their rate of division, or timing of differentiation. However, migration of late-born cortical neurons is delayed, with neurons stalling in the intermediate zone and exhibiting an abnormal multipolar morphology. This suggests that RA controls the multipolar-to-bipolar transition that occurs in the intermediate zone and allows neurons to start locomotion in the cortical plate. Our work also shows a role for RA in cortical lamination, as deep layers are expanded and a subset of layer IV neurons are not formed in the Raldh2-ablated mutants. These data demonstrate that meninges are a source of extrinsic signals important for cortical development.
Highlights
Induction events in the anterior neural plate define the embryonic forebrain
Using a Raldh2 conditional knockout (Raldh2cKO), we showed that loss of function of Raldh2 from the beginning of its expression in the meninges did not affect the formation of progenitor cells, including radial glial (RG) and intermediate neuronal progenitor (INP) cells, nor the birth of newborn neurons
By tracing the newborn neurons using in utero electroporation of a green fluorescent protein (GFP) marker, we showed that loss of Retinoic acid (RA) in the developing cerebral cortex transiently affected the migration of newborn neurons
Summary
Induction events in the anterior neural plate define the embryonic forebrain. At the beginning of corticogenesis, neuroepithelial (NE) cells give rise to radial glial (RG) cells ( called apical progenitors) located in the ventricular zone (VZ), which undergo symmetrical and proliferative divisions to self-renew. RG cells divide asymmetrically to produce post-mitotic neurons or intermediate neuronal progenitor (INP) cells. INP cells localise in the subventricular zone (SVZ), divide a few times (1-2), and differentiate into neurons (Götz and Huttner, 2005; Miyata et al, 2010; Noctor et al, 2004). Newborn neurons migrate through the intermediate zone (IZ) and eventually give rise, in an inside-out manner, to five cortical layers known as layers II to VI
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