Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 146 (1), 18-36

Development and Evolution of the Human Neocortex


Development and Evolution of the Human Neocortex

Jan H Lui et al. Cell.

Erratum in

  • Cell. 2011 Jul 22;146(2):332


The size and surface area of the mammalian brain are thought to be critical determinants of intellectual ability. Recent studies show that development of the gyrated human neocortex involves a lineage of neural stem and transit-amplifying cells that forms the outer subventricular zone (OSVZ), a proliferative region outside the ventricular epithelium. We discuss how proliferation of cells within the OSVZ expands the neocortex by increasing neuron number and modifying the trajectory of migrating neurons. Relating these features to other mammalian species and known molecular regulators of the mouse neocortex suggests how this developmental process could have emerged in evolution.


Figure 1
Figure 1. Progenitor Cell Expansion Can Underlie Neocortical Enlargement
Neuronal number is a key determinant of neocortex size and shape. Neurons are produced from a lineage of radial glia (RG) stem cells (red) and transit-amplifying intermediate progenitor (IP) cells (green). Expansion in one or both cell populations has been proposed as potential mechanisms that underlie neocortical expansion. Expansion of the founder RG cell population prior to the onset of neurogenesis (A) predicts a large ventricular zone (VZ). Expansion in the number of transit-amplifying divisions (B) predicts a large subventricular zone (SVZ).
Figure 2
Figure 2. Features of Human Neocortical Development
Cellular behaviors observed in the outer subventricular zone (OSVZ) show that the human neocortex uses expanded numbers of both stem and transit-amplifying cell types (radial glia [RG] and intermediate progenitor [IP] cells, respectively). (A) Cells expressing the neuronal markers NeuN (RBFOX3, red) and CTIP2 (BCL11B, green) make up ~45% of the OSVZ population (gestational week [GW] 15.5) but never colabel with the progenitor cell marker SOX2 (blue, inset). (B) The cell division and behavior of OSVZ radial glia-like (oRG) cells is illustrated. (C) The RG population increases through the generation of oRG cells from the ventricular zone (VZ) and their expansion in the OSVZ. Dashed lines indicate the unknown length of newborn radial fibers. (D) oRG daughter cells exhibit protracted differentiation and have an increased capacity for transit amplification. (E) The differentiation of oRG daughter cells is marked by the loss of SOX2 expression and Notch activation (HES1), with a gain in TBR2 expression. Together, these observations explain how the combination of oRG proliferation and differentiation expands the OSVZ over the course of midgestation and gives rise to an increased number of neurons. The lineage and molecular signatures of cells that form the OSVZ are shown (inset).
Figure 3
Figure 3. Different Rates of Neuron Accumulation as a Result of Different Modes of Progenitor Cell Division
The cellular mechanisms of human corticogenesis suggest that the outer subventricular zone (OSVZ) contains OSVZ radial glia-like (oRG) cells and an extended lineage of transit-amplifying intermediate progenitor (IP) cells. To illustrate the effect of these progenitor cells on the rate of neurogenesis, we model and contrast the outcomes in neuronal number from developmental schemes that utilize OSVZ proliferation versus ones that do not. In every case, we start with two radial glial (RG) cells and plot neuron number over the course of eight cell cycles. We also assume no cell death. (A) Neurons are directly born from RG through repeated rounds of asymmetric division. The rate of accumulation is linear at one neuron/cell cycle/RG cell (Rakic, 1988, 2009; Noctor et al., 2001). (B) We take into account how RG cells give rise to IP cells that undergo one transit-amplifying division. This delays birth of the first neuron by one cycle but thereafter accumulates cells linearly at a rate of two neurons/cell cycle/RG cell. This is the model for rodent corticogenesis (Noctor et al., 2004, 2008; Haubensak et al., 2004). (C) Transit amplification by IP cells is not taken into account, but ventricular RG (vRG) cells in the human are assumed to generate oRG cells by repeated rounds of asymmetric division. Once born, oRG cells divide repeatedly to generate one neuron per cell cycle. Because the number of oRG cells increases every cell cycle, this results in exponential growth of neuron number (Fietz et al., 2010; Fietz and Huttner, 2011). (D and E) One vRG cell undergoes a developmental scheme resembling the rodent (B), whereas the other generates oRG cells over repeated cell cycles. In addition to the exponential growth attributed to oRG cell accumulation, neuronal production is further amplified by two (D) or three (E) transit-amplifying cycles by each oRG-derived IP cell (Hansen et al., 2010). These plots highlight the differential effects of stem cell accumulation and extended transit amplification. We hypothesize that (E) is the most accurate model thus far, although there are several unknown parameters that should change the model. First, the number of transit-amplifying divisions in humans is unknown. Based on how the proportion of oRG cells to IP cells is ~2:3, we predict that the number of IP divisions does not exceed 3–4, as IP cells would be observed to greatly outnumber oRG cells. Second, the rate of oRG generation is a combined effect of generation from the VZ and expansion in the OSVZ. These parameters are not understood but presumably dictate the relative amount of linear versus exponential neuron production in the human.
Figure 4
Figure 4. Contrasting Rodent and Human Neocortical Development
(A) Current views of rodent corticogenesis are illustrated. Radial glial (RG) cells most often generate intermediate progenitor (IP) cells that divide to produce pairs of neurons. These neurons use RG fibers to migrate to the cortical plate. The historical view of neocortical development was that RG and neuronal progenitor cells were lineally distinct and that RG did not have a role in neurogenesis. Our current appreciation of the lineage relationship between RG cells, IP cells, and neurons has revised this view. The recent observation that small numbers of outer subventricular zone radial glia-like (oRG) cells exist in the mouse is also illustrated. (B) We highlight the lineage of oRG cells, IP cells, and migrating neurons (red to green) present in the human outer subventricular zone (OSVZ) and the increased number of radial fibers that neurons can use to migrate to the cortical plate. The number of ontogenetic “units” is significantly increased with the addition of oRG cells over ventricular RG (vRG) cells. Maintenance of oRG cells by Notch and integrin signaling is shown. Short neural precursors (SNP), a transitional cell form between RG and IP cells, are also depicted in (A) and (B). For simplicity, we do not illustrate all of the cell types described in Figure 2E.
Figure 5
Figure 5. Remodeling of the Radial Migration Scaffold in the OSVZ
We hypothesize that development of the outer subventricular zone (OSVZ) results in dramatic remodeling of the migration scaffold, where fibers no longer span the apical and basal surfaces. Radial glia (RG) fibers originate from both the ventricular zone (VZ) and OSVZ but may only extend part of the way to the pial surface, therefore forcing migrating neurons to switch fibers and disperse tangentially en route to the cortical plate. This mechanism may be important in the expansion of neocortical surface area observed in gyrencephalic species.
Figure 6
Figure 6. Molecular Mechanisms of Radial Glia Maintenance
(A) The basal fiber of radial glia (RG) cells (red) is important for the reception of Notch signaling from neuronally committed cells in the subventricular zone (SVZ) and secreted factors such as retinoic acid from the meninges. In particular, we show how the reception of Notch signaling in RG results in activity of the Notch intracellular domain (NICD), which promotes HES1/5 expression and leads to repression of the neuronal state. (B) We hypothesize that asymmetric distribution of Par3 (PARD3) and asymmetric inheritance of the basal fiber during RG mitosis result in differential Notch signaling and cell fate in the two daughters. Par3, a component of the apical complex, is distributed asymmetrically during mitosis and may contribute to asymmetric sequestration of NUMB, an inhibitor of Notch signaling, at cell-cell junctions. The daughter cell with less Par3 has higher levels of active NUMB that inhibits Notch signal, resulting in neuronal differentiation. Inheritance of the basal fiber may also help to enforce Notch signaling in only one of the daughter cells. We also highlight how removal of LGN (GPSM2) shifts vertical cleavages toward more oblique/horizontal ones, resulting in the production of outer subventricular zone radial glia-like (oRG) cells. (C) Adherens junction components (pink) are critical for controlling multiple pathways that define the intracellular signaling state of RG cells.
Figure 7
Figure 7. OSVZ Proliferation in the Context of Evolution
(A and B) A phylogenetic tree (adapted from the Tree of Life project [] and WhoZoo Project []) is shown to illustrate the diversity of brain size/shape in an evolutionary context. Eutherian (placental mammals) and metatherian (marsupial) species, the two major infraclasses of mammals, are included, whereas monotremes (egg-laying mammals), the other major order of extant mammals, are not. Species in which outer subventricular zone radial glia-like cells have been observed in embryonic tissues are labeled (oRG). Species that lack the oRG label have not yet been examined for the presence of these cells. Each eutherian superorder illustrated (A, orange) contains species that have lissencephalic (left) and gyrencephalic (right) brains (B, from the Comparative Mammalian Brain Collections []). Examples of both lissencephaly (armadillo) and gyrencephaly (sloth) also exist in the Xenarthra superorder (not shown). Thus, the evolution of gyrencephaly (or lissencephaly, as the case may be) was not an isolated event. oRG cells are present across multiple superorders, indicating that these features are not specific to a particular lineage of mammals. The degree of oRG-related proliferation and that of oRG-derived IP cells varies in different species and likely gives rise to diversity in neuronal number and brain shape. Images shown (B) are all coronal sections (not to scale) except for the elephant, which is a dorsal view

Similar articles

See all similar articles

Cited by 391 articles

See all "Cited by" articles

Publication types


LinkOut - more resources