Cell-cycle control and cortical development

“Because these distinct proliferative programmes generate areal differences prior to the arrival of thalamic fibres, they imply the presence of an intrinsic, defined developmental programme and are compatible with the concept of the protomap theor”

“It is counterintuitive that such a large increase in neocortical size is achieved by a substantial prolongation, rather than reduction in duration of the cell cycl”

“However, it remains unclear how prolonging G1 induces differentiation mechanistically, other than the hypothesis that because G1 is the period of the cell cycle in which cells are exposed to extrinsic differentiating stimuli, spending more time in G1 should arguably lead to an accumulation of cell fate determinants to…”

“1, H and I); (ii) cortical development starts at about E11 (20), which aligns well with the time points of potential fetal exposure to MIA (7); (iii) disorganized cortex and focal patches of abnormal laminar cytoarchitecture have been found in RESEARCH SCIENCE sciencemag.org 26 FEBRUARY 2016 • VOL 351 ISSUE 6276 933 1…”

“Through various morphogens that induce cell divisions along the apical surface of the ventricular zone, cortical progenitors are born from radial glia and undergo a series of symmetric and asymmetric cell divisions to give rise to the cellular diversity throughout the cortex (Dehay and Kennedy 2007).”

“Attempts have been made to integrate more recent observations into the Boulder Commitee's schem”

“The SLN model of cortical hierarchy emphasizes the specificity of the supragranular layers, which in mammalian evolution undergo an expansion to reach a maximum in primates (Dehay and Kennedy, 2007; Hill and Walsh, 2005; Rakic, 2009).”

“This led to the hypothesis that BP proliferation in the SVZ, and in particular the oSVZ, might be more strongly promoted by thalamocortical axon-derived mitogens in gyrencephalic as compared with lissencephalic species (Dehay and Kennedy, 2007).”

“Pixel density was then scaled linearly from 0 to 1 and pseudocolored.”

“In vitro experiments using mouse tissue suggest that TCAs release a diffusible mitogenic activity that promotes the production of both glia and neurons by explants of the cortical VZ (Dehay and Kennedy, 2007).”

“This could support the journey of neurons over the total thickness of the cortical wall, which is substantially increased in humans compared to non-human primates or rodents (Dehay and Kennedy, 2007; Rakic, 2009; Sidman and Rakic, 1973).”

“…and Human Cortex Examination of the timing of the macaque GZ suggested that high proliferative rates are required to maintain and amplify the OSVZ progenitor pool over the protracted period of supragranu-lar neuron production in the macaque (Dehay and Kennedy, 2007; Lukaszewicz et al., 2005).”

“Current knowledge of cellular and molecular mechanisms in brain development has so far mainly been obtained from studies on the rodent smooth-surfaced lissencephalic brain [6].”

“Defective INM may also lengthen the G1 phase of RGPCs and lead to more differentiative mitotic divisions, which are expected to reduce the number of IPCs and progenitors lining the VZ (Dehay and Kennedy, 2007).”

“Mouse outer VZ progenitors share cell properties with OSVZ progenitors in gyrencephalic mammals OSVZ progenitors are a different type of self-renewing progenitors implicated in cortical development in the primate and other gyrencephalic mammals (Kriegstein et al., 2006; Dehay and Kennedy, 2007).”

“Shortened cell cycle has previously been implicated in reduced responsiveness to differentiation signals and it has been suggested that cell-cycle regulation is an important control point for mechanisms that account for differences in neuron number between rodents and primate”

“This effect is strikingly in line with the expected pattern of human cortical neurogenesis compared with non-human primates: human cortical RG cells are expected to go through an increased number of self-renewing and/or proliferative cycles compared with non-human primates (Dehay and Kennedy, 2007; Geschwind and Rakic…”

“Changes in cell cycle length have been implicated in cell fate determination during neurogenesis [23].”

“(40% of cases) This histologic feature of the normal developing cerebral cortex is considered a sign of abnormal cortical development if identified in the postnatal brain (Dehay & Kennedy, 2007).”

“, and there are intriguing links between NPC cell-cycle length and neuron outpu”

“…enlargement of the brain, which has been related to an excessive production of progenitor cells and cortical neurons due to a decreased apoptosis, or a shortening of cell cycle and increased cell cycle re-entry (Dehay & Kennedy, 2007; Hansen et al , 2010; Wang et al , 2011; Barkovich et al , 2012).”

“This latter result begs the other question of how the counts should be interpreted, for at face value it suggests that there are major differences in the way that area 17 is assembled compared to all other cortical areas, but there are not (for review see Dehay and Kennedy, 2007).”

“One of the primary mechanisms that regulate neuroprogenitor divisions is the rate of cell cycle progression, particularly G1/S transition time 92, 93 .”

“Disruption of the dynamics of NPC or IPC proliferation and differentiation result in alterations in cell number, cellular identity, and organization of the cortex (Dehay and Kennedy, 2007).”

“In gyrated mammals, this radial expansion and lateral dispersion of neurons is achieved by a dramatic increase in neurogenic progenitor cells and the massive formation of bRG in the oSVZ, which are critical to lead radially migrating neurons into lateral dispersion (Dehay and Kennedy, 2007; Borrell and Reillo, 2012).”

“These observations and others (11, 12) led to the hypothesis that TG1 could be an integral part of a cellular mechanism regulating the mode of division (13, 14).”

“4a ), and the relationship between the cell cycle regulation and the fate control of radial glia has already been establishe”

“We and others have previously established that these potent cell cycle regulators are direct targets of ERK signaling and play important roles in progenitor proliferation (Calegari and Huttner, 2003; Dehay and Kennedy, 2007; Lange et al., 2009; Pucilowska et al., 2012).”

“(B) Immunostaining for TBR2, a marker for intermediate neuronal progenitors, at E14.”

“com contributing to arealization [9].”

“A rapid amplification of bRG would be responsible for expanding the primate OSVZ to its outstanding size, and to prepare it for an eventual tsunami of upper-layer neuron production [16,33,52].”

“In addition, the SVZ is preferentially expanded specifically during the time of upper-layer neurogenesis (Takahashi et al., 1999; Lukaszewicz et al., 2006; Martı́nez-Cerdeño et al., 2006; Dehay and Kennedy, 2007).”

“These progenitors are accommodated in additional germinal layers, like the inner and outer subventricular zone (i/oSVZ) 1–4 that are located basal to the ventricular zone (VZ), where progenitors are anchored at the ventricular surface (VS).”

“Indeed, considerably enlarged upper cortical layers characterize the primary visual area of the cortex in primates (for a review, see Dehay and Kennedy, 2007).”

“Studies have shown an inherent difference in cell-cycle kinetics between different regions at embryonic ages that lead to differences in cortical numbers (Dehay et al. 1993; Polleux et al. 1997; Dehay and Kennedy 2007).”

“Developmental Neurobiology Moreover, because cortical development in the lissencephalic mouse and rat does not include the formation of an OSVZ, this layer was believed to play a central role in the development of gyrencephaly (Smart et al., 2002; Dehay and Kennedy, 2007).”

“The IFL is a cell-poor zone filled with axon fascicles, which is commonly used to delimit ISVZ from OSVZ at late developmental stages (Smart et al. 2002; Dehay and Kennedy 2007).”

“…the formation of folds and fissures (Welker, 1990), and many of the critical features defining cortical progenitor cells (cell cycle, amplification, neurogenesis) vary significantly across such regions (Dehay et al , 1993; Lukaszewicz et al , 2005; Dehay & Kennedy, 2007; Reillo et al , 2011).”

“Given that the length of the G1 phase corresponds to a window of increased sensitivity to differentiation signals (Dehay and Kennedy, 2007), it is conceivable that shortening the G1 phase might contribute to the maintenance of the undifferentiated state of GSCs, as previously proposed for mammalian embryonic stem cell…”

“Cortical neurogenesis is associated with progressive lengthening of the cell cycle and results in increased fraction of progenitors that exit the cell cycle and differentiate (Dehay and Kennedy, 2007; Gotz and Huttner, 2005).”

“Our findings thus support a combination of the “protomap” and “protocortex” models of specification of cortical areas (Dehay and Kennedy, 2007), one in which two zones are specified in the gray matter that differ in how neurons are added to the developing cortex, followed by functional…”

“Two principal parameters determine how many of these divisions occur during cortical neurogenesis: (1) how often a given PC undergoes neurogenic divisions and (2) how many PCs capable of undergoing neurogenic division (neuronal PCs) are formed (Caviness et al., 1995; Dehay and Kennedy, 2007; Huttner and Kosodo, 2005;…”

“The oSVZ compartment becomes very prominent in primates, including humans, and contains detached RGCs (11), recently renamed as outer radial glia (oRG) or basal radial glia (bRG) (5).”

“inside-out assembly of the 6-layered cortex (Smart 1973; McConnell 1995; Kriegstein et al. 2006; Rakic 2006; Cheung et al. 2007; Dehay and Kennedy 2007; Pontious et al. 2008).”

“Prolonged proliferation in the primate-specific outer SVZ (Lukaszewicz et al., 2006; Dehay and Kennedy, 2007), is temporally matched with emergence of enlarged supragranular layers (layers II–IV) in primates (Hill and Walsh, 2005).”

“This article is an open access publication SVZ (OSVZ) by the inner fiber layer (IFL) in primates (Dehay and Kennedy, 2007; Hansen et al., 2010; LaMonica et al., 2012;Garcia-Morenoet al., 2012).”

“At the onset of neurogenesis, these so-called apical progenitor cells (Dehay and Kennedy 2007; Fietz and Huttner 2011) divide asymmetrically producing either a neuron or two other types of progenitor cells, namely basal radial glia (bRG) or intermediate progenitor cells (IPCs).”

“ventricular zone (VZ) and subventricular zone (SVZ) in a temporally regulated manner (Dehay and Kennedy 2007).”

“, suggesting that some in vivo cues required for the generation of a complete repertoire upper layer neurons are missing in vitro”

“The fitness parameter defines the relative probability of the given cell-type to be chosen for division.”

“Although most radial glial cells have a short cell cycle during development ranging between 10 and 18 h (Götz and Huttner 2005; Dehay and Kennedy 2007; Lange and Calegari 2010; Arai et al. 2011), most adult radial glial cells in the SEZ and subgranular zone (SGZ) of the DG have a much longer cell-cycle length ranging…”

“The fate of neurons and laminar cytoarchitecture in each specific area determines their function: the adult primary motor cortex contains a large number of CSMN and has a thick layer V; the primary somatosensory area is characterized by a thick layer IV, where the neurons that receive relayed sensory inputs are locate…”

“Indeed, changes in Ts across the period of cortical neurogenesis have been observed in primates, in which biphasic modulation of Ts has been related to cortical expansion and “laminar elaboration” (Kornack and Rakic, 1998; Dehay and Kennedy, 2007).”

“Divisions of aRG are initially rapid and then slow down as corticogenesis unfolds [from 8 hours at the early stages to 18 hours at the end of corticogenesis in mice and from 23 to 54 hours in primates (16, 17)].”

“In general, feedback regulation by postmitotic neurons onto earlier stages enables a tissue to control the total cell number and the proportions of differentiated cell type”

“Changes in cell-cycle length have previously been implicated in altered cell-cycle progression (Dehay and Kennedy, 2007; Kim et al., 2009; Qu et al., 2013).”

“Furthermore, given its capacity to influence progenitor cell renewal, Cyclin D2 lends itself for evolutionary selection to increase the number of cell cycles (known to occur in primates) for generating a larger cortex (Finlay and Darlington, 1995; Rakic, 1995; Dehay and Kennedy, 2007), or within a”

“The timing of neuronal differentiation by stem/progenitor cells in the telencephalon is regulated by the timing of cell cycle exit, such that over-expression of cyclin D prolongs the proliferation of undifferentiated cells and delays the onset of neurogenesis (Dehay and Kennedy, 2007; Lange et al., 2009).”

“Specifically, the subventricular zone (SVZ) is greatly expanded in gyrencephalic primates and can be subdivided into an inner and outer region, the latter of which is negligible in lissencephalic rodents (Smart et al., 2002; Lukaszewicz et al., 2005; Zecevic et al., 2005; Dehay and Kennedy, 2007; Bayatti et al., 2008;…”

“These results suggest that regional specification is already established at the developmental stage, in line the cortical protomap concept.(72,80) How, then, does the developing human cerebral cortex generate such a large number of neurons? There are two parameters that, as a matter of principle, determine the number…”

“Cyclin D1 is a regulatory oncogene that initiates cell cycle entry in a variety of physiologic and pathologic biologic processes.(15) This is especially true during the proliferative phase of neurogenesis that occurs during the embryonic period in rodents, when apoptosis occurs in more than 50% of proliferating cells…”

“…period could be linked to species-specific properties intrinsic to neural progenitors, such as differential cell cycle control or tuning of self-renewal versus terminal differentiation (Lukaszewicz et al., 2005), but overall the underlying mechanisms remain unknown (Dehay and Kennedy, 2007).”

“5, neuronal progenitor cells still proliferate in the ventricular zone of the cerebral cortex (Dehay & Kennedy, 2007).”