Embryonic and Early Fetal Development of the Human Neocortex

Abstract

Early corticogenesis was studied in human embryos and early fetuses from Carnegie stages 16 to 22 (5-8 gestational weeks) by using immunohistochemistry for Reelin (Reln), calretinin (CR), and glutamic acid decarboxylase (GAD). A first population of Reln-positive cells appears in the neocortical anlage at stage 16 and increases in number at stages 17-18. At stages 19-20, a monolayer of horizontal CR- and GAD-positive, Reln-negative neurons forms in the preplate, whereas Reln-positive cells shift into a subpial position. Another cell class, the pioneer projection neuron, is CR-positive but GAD- and Reln-negative; pioneer cells contribute early corticofugal axons. Pioneer cells first appear below the monolayer at stage 20 and form a pioneer plate at stage 21. The cortical plate (CP) proper emerges at stage 21 and inserts itself within the pioneer plate, which is thus split into a minor superficial component and a larger deep component that presumably corresponds to the subplate. Initial CP neurons are radially organized and mostly CR-negative. Reln-positive cells remain consistently segregated from the pioneer cells and are thus not directly involved in preplate partition. Our data indicate that the neuronal composition of the human neocortical preplate is more complex than generally described and that various neurons participate in a sequence of events that precede the emergence of the CP.

Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder

“…62 Although no evidence has thus far been produced directly linking the triplet repeat to transcriptional or translational efficiency, the CG-rich 5Ј UTR encompassing the polymorphic GGC repeat suggests the existence of strong transcriptional regulation, which might be even tighter in the presence of 'long' alleles. Interestingly, Reelin mRNA transcripts are first detected at E8.5 in mice, 63 but Reelin protein becomes detectable at the extracellular level only around E13, 25 similarly, neocortical Reelin protein in humans can be detected starting around the 5th week of gestation, 64 this timing strikingly coincides with the recently-proposed time window of maximal vulnerability to autism-inducing agents. 16 This model indeed holds some heuristic potential, but must be viewed with caution until the role of triplet repeat alleles in RELN gene expression will be definitively proven by ongoing in vitro experiments.…”

Generation of Reelin-Positive Marginal Zone Cells from the Caudomedial Wall of Telencephalic Vesicles

“…The concept of a dual origin of the cerebral cortex, together with the classical concept from the time of Ramó n y Cajal, provided a prevailing view that both reelin-positive cells and subplate are generated as preplate from the underlying VZ before the formation of CP (Marín-Padilla, 1978, 1998. Consistent with these ideas, several studies suggest the local generation of reelin-positive cells within the neocortical area (Meyer et al, 2000;Hevner et al, 2003). In contrast, several lines of evidence suggest that neocortical reelinpositive cells may originate from locations extrinsic to the neocortex (Meyer et al, 1998(Meyer et al, , 2002Lavdas et al, 1999;Shinozaki et al, 2002).…”

Early history of subplate and interstitial neurons: from Theodor Meynert (1867) to the discovery of the subplate zone (1974)

“…These findings clearly show that an initial description of the subplate as layer VIb in the fetal cat (Marin-Padilla, 1971, 1972, 1978 was overly simplified and that it at best can only be applied to the first (earliest generated) wave of subplate neurons. For a detailed criticism of this original concept of the primordial plexiform layer (or preplate) see a recent review (Bystron et al 2008) as well as a number of recent studies which pointed out a previously unsuspected complexity of the early neocortical anlage in humans (Zecevic et al 1999;Meyer et al 2000;Zecevic & Rakic, 2001;Rakic & Zecevic, 2003;Bystron et al 2005Bystron et al , 2006 as well as in rodents (Rickmann et al 1977;Hevner et al 2003;Jimé nez et al 2003;Bielle et al 2005;García-Moreno et al 2007). …”

“…In fact, it has been repeatedly pointed out that the developmental history of the subplate is very different in humans and other primates than in carnivores and rodents (Kostović & Rakic, 1980, 1990Meyer et al 2000;Smart et al 2002;Lukaszewicz et al 2005;Molná r et al 2006;Meyer, 2007;Bayatti et al 2008;Bystron et al 2008;Suá rez-Solá et al 2009). For example, in contrast to the situation in rodents, neurons are continuously added to the subplate in primates during the later stages of corticogenesis (Kostović & Rakic, 1990;Smart et al 2002;Meyer, 2007;Bystron et al 2008).…”