Proliferation control in neural stem and progenitor cells

Abstract

Neural circuit function can be drastically affected by variations in the number of cells that are produced during development or by a reduction in adult cell number owing to disease. For this reason, unique cell cycle and cell growth control mechanisms operate in the developing and adult brain. In Drosophila melanogaster and in mammalian neural stem and progenitor cells, these mechanisms are intricately coordinated with the developmental age and the nutritional, metabolic and hormonal state of the animal. Defects in neural stem cell proliferation that result in the generation of incorrect cell numbers or defects in neural stem cell differentiation can cause microcephaly or megalencephaly.

Figure 1. Drosophila melanogaster and mouse neural stem cell lineages

(A) D. melanogaster neuroblasts (NBs) divide asymmetrically to self-renew and to generate a more differentiated daughter cell. The Par complex (green) localizes to the apical cortex of NBs, and directs the cell fate determinants Mira, Numb, Pros and Brat (orange) to the basal cell cortex. The apical Par complex orients the mitotic spindle with respect to the established apical-basal axis. The NB divides asymmetrically and segregates the basal cell fate determinants into the ganglion mother cell (GMC), in which they promote differentiation. (B) A 3^rd instar D. melanogaster larval brain. The larval brain can be divided into the central brain (CB), optic lobe (OL) and ventral nerve cord (VNC). Several types of NBs (including type I, type II and mushroom body (MB) NBs) can be found in the CB and in the thoracic and abdominal regions of the VNC. (C) Lineage organization of type I and type II NBs. Type I NBs divide to self-renew and to generate a GMC, which divides once more to form two neurons (N). Type II NBs divide to self-renew and to generate an immature intermediate progenitor (iINP). INPs undergo through a period of maturation (to form a mature INP (mINP)) with no cell division, after which they undergo several rounds of division to self-renew and generate GMCs. Each GMC divides symmetrically to form two neurons or glia. (D) Development of the mouse neocortex. Before the onset of neurogenesis neuroepithelial cells (NE, dark blue line in panel B) divide symmetrically to expand their number. When neurogenesis begins NE transform into radial glia (RG) cells that can divide to self-renew and generate a neuron (direct neurogenesis) or divide to self-renew and generate an intermediate progenitor cell (IPC) that can then divide to generate neurons (indirect neurogenesis). RG cells can also divide to generate outer radial glia (oRG) cells that can themselves divide to self-renew and generate IPC or neurons. CP-cortical plate; IZ-intermediate zone; N- neuron; SVZ-sub-ventricular zone; VZ-ventricular zone.

Figure 2. Asymmetric cell division in the mammalian neocortex

(A-C) Proposed models of radial glia (RG) cell asymmetric cell fate generation (A) Asymmetric inheritance of differently aged centrioles (the ‘mother’ centriole being older than the ‘daughter’ centriole) into the two daughter cells could determine their differential fate. (B) Different levels of Notch signaling between the RG and the differentiating intermediate progenitor cells (IPC) and neurons are an important regulator of cell fate. This may arise as a result of lateral inhibition, which proposes that the differentiating cell with higher expression of the Notch ligands, promotes self-renewal of the neighboring cell. (C) Notch signaling is also an important regulator of symmetric RG divisions. At early stage of neurogenesis RG cells express both Notch ligands and receptors, and this way activate Notch signaling in neighbouring RG cells, promoting their RG cell fate. (D) During mid-neurogenesis, IPCs provide Notch ligands to RG to promote their self-renewal. (E) Notch signaling results in an oscillatory pattern of expression of Notch target Hes1 and proneural genes Ngn2 and Dll-1 in self-renewing cells. In differentiating neural cells, the oscillations cease and cells express low levels of Notch targets and high levels of proneural genes promoting differentiation. (F) Cell cycle length can influence neural cell fate. S phase is shorter in asymmetrically dividing RGs comparing to self-renewing cells. Dll-Delta like; IPC-intermediate progenitor cell; NSC-neural stem cell.

Figure 3. Different stages of Drosophila neurogenesis

(A) Different stages of Drosophila neurogenesis. NBs (blue) are generated during embryonic development; enter quiescence at the embryo to larva transition; re-enter the cell cycle in early larval stages; and cease proliferating during pupal stages. Embryonic and pupal NBs do not increase back to the size of their parent NB after each asymmetric cell division, whereas larval NBs do re-grow. (B) NB exit from quiescence in early larval stages is triggered by larval feeding. Amino acids are sensed by the receptor Slimfast (Slif) in the fat body. Slif activates the TOR pathway and the release of a fat body derived signal (FDS). The FDS stimulates glial cells to secrete Insulin like peptides (dILPs) that activate Insulin signaling and PI3K/TOR signaling in NBs and consequently their proliferation. (C) The switch from growing larval NBs to shrinking pupal NBs is triggered by a pulse of Ecdysone (Ecd) at the larva to pupa transition. Ecd is produced and released by the prothoracic gland (PG), a component of the ring gland. The secreted Ecd binds to its receptor, EcR, in NBs where it induces this change in NB growth properties and, ultimately, NB disappearance.

Figure 4. Metabolic regulation of neural stem cell fate and proliferation

(A) In Drosophila melanogaster, a pulse of the steroid hormone Ecdysone (Ecd) induces global transcriptional changes in metabolic genes causing a shift in the metabolic profile between larval and pupal neuroblasts (NBs). In pupal NBs, Ecd/EcR together with the Mediator complex change the transcription levels of several metabolism enzymes which results in an increase in Oxidative phosphorylation (OxPhos) and in a decrease in glycolysis. Larval NBs thus depend highly on glycolysis, whereas pupal NBs depend on OxPhos. Highly glycolytic metabolism is thought to promote bio-synthesis of macromolecules and therefore cell growth. By contrast, metabolism that is dependent on OxPhos can produce more energy at the expense of intermediate metabolites and bio-synthesis. (B) The highly proliferative mouse adult neural stem cells (NSCs) have high expression of FASN and low expression of Spot14 enzymes, which leads to high levels of fatty acid synthesis. By contrast, low proliferating mouse adult NSCs have the opposite pattern of expression of FASN and Spot14, and have therefore low levels of fatty acid synthesis. High levels of fatty acids promote bio-synthesis of macromolecules required for NSCell growth and proliferation. EcR-Ecdysone receptor; Med-Mediator.