Development of the Entorhinal Cortex Occurs via Parallel Lamination During Neurogenesis

Abstract

The entorhinal cortex (EC) is the spatial processing center of the brain and structurally is an interface between the three layered paleocortex and six layered neocortex, known as the periarchicortex. Limited studies indicate peculiarities in the formation of the EC such as early emergence of cells in layers (L) II and late deposition of LIII, as well as divergence in the timing of maturation of cell types in the superficial layers. In this study, we examine developmental events in the entorhinal cortex using an understudied model in neuroanatomy and development, the pig and supplement the research with BrdU labeling in the developing mouse EC. We determine the pig serves as an excellent anatomical model for studying human neurogenesis, given its long gestational length, presence of a moderate sized outer subventricular zone and early cessation of neurogenesis during gestation. Immunohistochemistry identified prominent clusters of OLIG2+ oligoprogenitor-like cells in the superficial layers of the lateral EC (LEC) that are sparser in the medial EC (MEC). These are first detected in the subplate during the early second trimester. MRI analyses reveal an acceleration of EC growth at the end of the second trimester. BrdU labeling of the developing MEC, shows the deeper layers form first and prior to the superficial layers, but the LV/VI emerges in parallel and the LII/III emerges later, but also in parallel. We coin this lamination pattern parallel lamination. The early born Reln+ stellate cells in the superficial layers express the classic LV marker, Bcl11b (Ctip2) and arise from a common progenitor that forms the late deep layer LV neurons. In summary, we characterize the developing EC in a novel animal model and outline in detail the formation of the EC. We further provide insight into how the periarchicortex forms in the brain, which differs remarkably to the inside-out lamination of the neocortex.

Prenatal development of the human entorhinal cortex

“…In addition, GABAergic neurons originate from neural progenitors of the medial and caudal ganglionic eminence and migrate to the pallium until arriving in either the MZ or the SP from where they finally get the corresponding fate inside the CP (Marín & Rubenstein, 2001;2003). It would thus be of interest to study the development of GABAergic neurons as well to see whether and how their distribution influences the model proposed here, and to which extent it is supported by the above-mentioned studies in mice and pigs (Donato et al, 2017;Liu et al, 2021).…”

“…Our results obtained with NeuN immunohistochemistry (Figure 12), also clearly refute the development of the EC in humans in an inside-out manner and support the early development of layer II and a key role of the large "promoter" neurons appearing in that layer first in the RM parts of the EC at about 13-13.5 w.g. (Kostović et al, 1993), followed by the other layers, possibly in a "parallel" pattern as described by Liu et al (2021), and possibly also with a "sandwich" gradient described by Bayer et al (1993), which suggests that after layer II and layers V/VI, layer III forms last (Bayer et al, 1993). Altogether, these findings suggest that the final thickness and arrangement of EC layers in its different subfields along with the presence or absence, and position of LD, cannot be simply calculated based on the number of neurons in each radial unit, differential time of origin, and rate of migration along the radial glial cells (Rakic, 1988).…”

“…As assessed through monitoring of the doublecortin (a microtubule‐associated protein uniquely associated with immature neurons) expression, stellate cells in layer II of the MEC were the first to mature, followed by pyramidal cells in MEC layer II, CA1, dentate gyrus (DG), subiculum, layer V of MEC and LEC and layer II of the LEC. One of the latest studies that used bromodeoxyuridine labeling in the porcine brain, which, in comparison with rodents, better corresponds to the timing of neurogenesis in humans (7–17 w.g., Kostović et al., 2019), has revealed that the deeper layers of the MEC (V/VI) form first, but in parallel and thereafter the superficial MEC layers (II/III), with some layer II neurons forming last; a process termed parallel lamination (Liu et al., 2021). In comparison with the neocortex, parallel lamination of the MEC suggests that lamination of the EC differs significantly from the classic inside‐out lamination of the neocortex (Bayer, 1980; Liu et al., 2021).…”

“…One of the latest studies that used bromodeoxyuridine labeling in the porcine brain, which, in comparison with rodents, better corresponds to the timing of neurogenesis in humans (7–17 w.g., Kostović et al., 2019), has revealed that the deeper layers of the MEC (V/VI) form first, but in parallel and thereafter the superficial MEC layers (II/III), with some layer II neurons forming last; a process termed parallel lamination (Liu et al., 2021). In comparison with the neocortex, parallel lamination of the MEC suggests that lamination of the EC differs significantly from the classic inside‐out lamination of the neocortex (Bayer, 1980; Liu et al., 2021).…”

In utero exposure to maternal anti–aquaporin-4 antibodies alters brain vasculature and neural dynamics in male mouse offspring

“…Note that BBB impairment was specific to the entorhinal cortex. The entorhinal cortex is one of the first cortical regions to initiate neurogenesis ( 76 ), and AQP4 is highly expressed in adult entorhinal cortex ( 77 ), possibly making it more vulnerable to the effect of circulating AQP4-IgG during a critical time of development.…”