Proliferation and apoptosis in the developing human neocortex

Abstract

The cell kinetics of the developing central nervous system (CNS) is determined by both proliferation and apoptosis. In the human neocortex at week 6 of gestation, proliferation is confined to the ventricular zone, where mitotic figures and nuclear immunoreactivity for proliferating cell nuclear antigen (PCNA) are detectable. Cell division is symmetric, with both daughter cells reentering mitosis. At week 7, the subventricular zone, a secondary proliferative zone, appears. It mainly gives rise to local circuit neurons and glial cells. Around week 12, the ventricular and subventricular zones are thickest, and the nuclear PCNA label is strongest, indicating that proliferation peaks at this stage. Thereafter, asymmetric division becomes the predominant mode of proliferation, with one daughter cell reentering mitosis and the other one migrating out. Towards late gestation, the ventricular and subventricular zones almost completely disappear and proliferation shifts towards the intermediate and subplate zones, where mainly glial cells are generated. A remnant of the subventricular zone with proliferative activity persists into adulthood. In general, proliferation follows a latero-medial gradient in the neocortex lasting longer in its lateral parts. Apoptotic nuclei have been detected around week 5, occurring in low numbers in the ventricular zone at this stage. Apoptotic cell death increases around midgestation and then spreads throughout all cortical layers, with most dying cells located in the ventricular and subventricular zones. This spatial distribution of apoptosis extends into late gestation. During the early postnatal period, most apoptotic cells are still located in the subcortical layers. During early embryonic development, proliferation and apoptosis are closely related, and are probably regulated by common regulators. In the late fetal and early postnatal periods, when proliferation has considerably declined in all cortical layers, apoptosis may occur in neurons whose sprouting axons do not find their targets. Anat Rec 267: 261-276, 2002.

Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS

“…4Ai). This observation is consistent with previous reports identifying this region as a niche for pluripotent cells from which neural progenitor cells are generated (Chan et al, 2002, Gotz and Huttner, 2005, Stanger, 2008a, Stanger, 2008b. Embryos injected with Kv1.5 (hyperpolarizing) mRNA into the dorsal two cells at four-cell stage (for targeting neural tissues) significantly decreased the H3P signal in the embryonic brain in comparison to the controls ( Fig.…”

“…2Ai). This pattern of apoptosis in the developing brain is consistent with previous reports of a low background of apoptosis involved in proper brain development (Chan et al, 2002, Nonomura et al, 2013, Rakic and Zecevic, 2000. Embryos injected with Kv1.5 (hyperpolarizing) mRNA into the dorsal two cells at four-cell stage (ii,iii) …”

“…In addition to apoptosis, proliferation is a major factor regulating tissue boundaries and organ size during development and regeneration (Chan et al, 2002, Joseph and Hermanson, 2010, Shitamukai and Matsuzaki, 2012, Stanger, 2008a, Stanger, 2008b. Our previous study showed that V mem affects proliferation in the developing brain (Pai et al, 2015), as it does in a number of normal and neoplastic tissues (Blackiston et al, 2011, Blackiston et al, 2009, Chernet and Levin, 2013a, Ding et al, 2012, Higashimori and Sontheimer, 2007, Nilius and Wohlrab, 1992, Yang and Brackenbury, 2013.…”

Computational models of ethanol‐induced neurodevelopmental toxicity across species: Implications for risk assessment

“…Briefly, this dataset shows decreasing effects of ethanol on the proliferation rate over the 7-day period of neurogenesis in the rat. Here, we stretch this rodent dataset of ethanol-induced inhibition during neocortical neurogenesis to fit the 60-day period of monkey neocortical neurogenesis (Kornack, 2000) and 84 days of human neocortical neurogenesis (Chan et al, 2002). These simulations rely on the hypothesis that the developmental timing and peak daily exposure to ethanol during neurogenesis are the salient dose metrics, as has been shown in other studies (Driscoll et al, 1990;Maier and West, 2001).…”

S/MAR-binding properties of Sox2 and its involvement in apoptosis of human NT2 neural precursors

“…It occurs during the closure of neural tube, 36 during the development of mesencephalic region 20 and during corticogenesis, 37 and it is the balance between two genetically controlled processes, proliferation and apoptosis, that ensures the correct cell number in the developing CNS. 38 In conclusion, many nuclear DNA-binding proteins, whether they are transcription factors like Sox2, DNA repair enzymes like topoisomerase II and PARP, or nuclear matrix proteins like SATB1, undergo proteolysis during the process of apoptosis. Their binding sites conceivably lie within the unpaired regions of nuclear DNA, especially since some of them preferentially bind distorted or bent DNA, leaving these sites vulnerable.…”