856.2 The NSC Microenvironment During Embryogenesis
As already mentioned NSCs operate in microenvironments with limited presence of
extra-neural elements; thus, they are surrounded and remain in direct contact mostly
with other NSCs and their progeny. An interesting example of how these cells inter-
act with each other at the very early stages of development in order to shape the
nervous system is the phenomenon of lateral inhibition that has been described in
Drosophila melanogaster (Hartenstein and Wodarz 2003 ). Within the homogeneous
pool of neuroectodermal cells, that all express proneural genes, individual cells
show activation of Notch ligands (such as Delta) that act upon their immediate
neighbours and instruct them to downregulate proneural gene expression. Only
these, stochastically selected, cells progress towards becoming NSCs that delami-
nate from the neuroectoderm and initiate a program of asymmetric neurogenic divi-
sions (Isshiki et al. 2001 ).
6.2.1 One NSC, Three Microenvironments
During mammalian neurogenesis, NSC bodies are densely packed as a pseudolay-
ered epithelium that forms the neural tube. In the developing mouse cerebral cortex
and up to embryonic day (E) 11 these cells are called neuroepithelial (NEP). They
express Sox2 and nestin and because they undergo mitosis only when positioned at
the surface of the ventricle (initially the lumen of the neural tube that progressively
expands to form the brain ventricles) their nuclei remain in constant movement,
migrating away and towards the ventricle (a phenomenon called interkinetic nuclear
migration) in order to allow enough space for cell division. NEP cells are bipolar,
with a short apical process always remaining in contact with the ventricle and a
longer basal process remaining in contact with the pial surface (Fig. 6.1a); however,
recently an alternative architecture was described to occur in the ventral forebrain
with the basal process ending on a blood vessel (Tan et al. 2016 ) (see also section
6.2.3). The length of this basal process constantly increases as new layers of neural
stem and progenitor cells as well as of neurons and glia are formed. NEP cells
divide almost exclusively in a symmetric self-renewing mode in order to expand
their population, creating the so called ventricular zone (VZ). After E11, possibly in
order to adjust to the ever increasing width of the cortex, NEP cells acquire more
glial characteristics becoming radial glial cells (RGCs). These retain the bipolar
shape, with the basal process becoming much longer (Fig. 6.1a), express additional
markers such as the transcription factor Pax6 and the glial proteins BLBP (Fig. 6.1b)
and GLAST and exhibit a wide range of cell-division types with the asymmetric,
self-renewing being the dominant (Johansson et al. 2010 ). The tightly packed NEP
cells and RGCs of the VZ can support their self-renewal in an autocrine manner,
both in humans and rodents (Fietz et al. 2012 ). In addition, their cell bodies are sur-
rounded by an ECM rich in laminins, Tenascin-C and glycosaminoglycans but poor
6 Being a Neural Stem Cell: A Matter of Character But Defined...