Length of the Neurogenic Period—A Key Determinant for the Generation of Upper-Layer Neurons During Neocortex Development and Evolution

Abstract

The neocortex, a six-layer neuronal brain structure that arose during the evolution of, and is unique to, mammals, is the seat of higher order brain functions responsible for human cognitive abilities. Despite its recent evolutionary origin, it shows a striking variability in size and folding complexity even among closely related mammalian species. In most mammals, cortical neurogenesis occurs prenatally, and its length correlates with the length of gestation. The evolutionary expansion of the neocortex, notably in human, is associated with an increase in the number of neurons, particularly within its upper layers. Various mechanisms have been proposed and investigated to explain the evolutionary enlargement of the human neocortex, focussing in particular on changes pertaining to neural progenitor types and their division modes, driven in part by the emergence of human-specific genes with novel functions. These led to an amplification of the progenitor pool size, which affects the rate and timing of neuron production. In addition, in early theoretical studies, another mechanism of neocortex expansion was proposed—the lengthening of the neurogenic period. A critical role of neurogenic period length in determining neocortical neuron number was subsequently supported by mathematical modeling studies. Recently, we have provided experimental evidence in rodents directly supporting the mechanism of extending neurogenesis to specifically increase the number of upper-layer cortical neurons. Moreover, our study examined the relationship between cortical neurogenesis and gestation, linking the extension of the neurogenic period to the maternal environment. As the exact nature of factors promoting neurogenic period prolongation, as well as the generalization of this mechanism for evolutionary distinct lineages, remain elusive, the directions for future studies are outlined and discussed.

Teleost Fish and Organoids: Alternative Windows Into the Development of Healthy and Diseased Brains

“…In these animals, the BP of the SVZ can sustain multiple rounds of divisions to generate other precursor cells before dividing into neurons ( Götz and Huttner, 2005 ; Lui et al, 2011 ; Florio and Huttner, 2014 ). Indeed, the increase in the number of the BP outer RG cells (oRG) originating from aRG, and their proliferative potential has been proposed as a contributor for the increase in cortex size ( Nonaka-Kinoshita et al, 2013 ; Fernández et al, 2016 ), but it does not seem to be sufficient, given the presence of lissencephalic animals with a high number of BP ( Kelava et al, 2013 ; Stepien et al, 2021 ). Seminal works in the past years have demonstrated that a variety of morphology exists among BP cells even in the same species and that this instead might be a key factor determining neocortical expansion ( Betizeau et al, 2013 ; Kalebic et al, 2019 ).…”

“…Sustained gliogenesis in the outer SVZ has been implicated in the expansion of the neuropile, and therefore, the neocortex convolutions in primates ( Rash et al, 2019 ). Of note, the genetic bases of such peculiarity of precursor cell types for neocortex expansion are mapped using gyrencephalic models ( Florio et al, 2015 , 2016 ; Cárdenas and Borrell, 2020 ; Heide et al, 2020 ; Stepien et al, 2021 ). At the signaling level, a number of pro-proliferative molecules from -and interacting with-the ECM niche of the progenitor pool, likely involving Pi3K-AkT, mTOR, and MAPK signaling pathways, is being recognized as a crucial trigger for the distinctive proliferative capacity of BP cells as well as for their positioning in the developing cortex ( Sheppard and Pearlman, 1997 ; Fietz et al, 2012 ; Moreno-Layseca and Streuli, 2014 ; Cavallin et al, 2018 ; Heinzen et al, 2018 ; Long et al, 2018 ; Kalebic et al, 2019 ; Subramanian et al, 2020 ; Kyrousi et al, 2021 ).…”

“…Within the developing pallium, a precise balance and timing of signaling drive neural fate commitment and patterning, as well as the rate of progenitor pools’ expansion (level 1), migratory behavior and differentiation (level 2), and the establishment of connectivity patterns (level 3). Fine changes in local patterning schemes and precursor cells’ behavior across evolution underlie the array of diversity in vertebrate cognitive capabilities and the formation and expansion of the multilayered cytoarchitecture of the mammalian cortex, responsible for high-order functions typical of humans ( Striedter, 2005 ; Van Essen et al, 2018 ; Stepien et al, 2021 ). From a comparative point of view, mechanisms of cortex development at the level of repertoire of stem cells and proliferation strategies vary drastically even within closely related species of vertebrates and underly size and folding variation.…”

“…From a comparative point of view, mechanisms of cortex development at the level of repertoire of stem cells and proliferation strategies vary drastically even within closely related species of vertebrates and underly size and folding variation. The molecular roots of these differences are intensely studied by employing lissencephalic (harboring smooth brain) and gyrencephalic mammalians (showing superficial foldings and therefore expansion of the neocortex) ( Lui et al, 2011 ; Dehay et al, 2015 ; Florio et al, 2015 , 2016 ; Kalebic et al, 2019 ; Stepien et al, 2021 ). Furthermore, the presence of a homologous domain giving rise to the neocortex within the pallium territory in non-mammalian vertebrates is equally debated and little consensus exists to this day ( Northcutt, 1995 ; Wullimann and Mueller, 2004 ; Medina and Abellán, 2009 ; Nieuwenhuys, 2009 ).…”

Timing as a Mechanism of Development and Evolution in the Cerebral Cortex

“…The resultant model predicts that the timing of the switch from proliferative to neurogenic divisions produces the highest variation in final cortical numbers and is therefore potentially a strong driver of final brain morphology between species [Picco et al, 2018]. It is therefore clear that the timing and kinetics of neurogenesis vary across extant species, and that these changes correlate with altered brain morphology [Iwata, 2021;Stepien et al, 2021]. The causative role of these relationships can be inferred from experimental manipulations within the mouse, e.g.…”