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Keywords Neural stem cell • Development • Evolution • Extracellular matrix
- Vasculature • Cancer
6.1 Intrinsic vs. Extrinsic Regulation
The emergence of neural tissue has been an early event during evolution, having
occurred in pre-bilaterian animals. Irrespective of being a small network of neurons,
or an extremely elaborate neuroglial system, as in the avian and the mammalian
CNS, the nervous tissue is built by neural progenitors. These can be either loosely
specified cells within an epithelium, or more distinct neural stem cells that undergo
a well-controlled scenario of symmetric and asymmetric divisions before generat-
ing differentiated cells (reviewed in Hartenstein and Stollewerk ( 2015 )). By focus-
ing on the basic similarities or the vast differences of neurogenic processes across
evolution, it can be hypothesized that the identity and the properties of neural stem
cells (NSCs; in this review the term will be applied for any cell directly or indirectly
giving rise to mature neurons and glia) are largely inherent, or mostly dependent on
micro-environmental cues; both statements being equally strong.
The conserved expression of transcription factors of the SoxB gene family, as
well as the ability of both very primitive and very recent NSCs to generate neurons
with shared characteristics (e.g. expression of synaptotagmin), indicate that being a
NSC is most probably a matter of character, installed within the hard wiring of early
neuroectodermal/neuroepithelial specification. This introduces a first question to be
debated: Does the epithelial to neuroepithelial transformation depend on external
cues? The classical view is that small parts of the mesoderm, outside the neuroepi-
thelial anlage (for example the organizer or the node of amniotes) induce the neural
fate through the Bone Morphogenetic Protein (BMP) and Int/Wingless (Wnt) sig-
nalling pathways (Hartenstein and Stollewerk 2015 ). Notably though, Van der Kooy
and his team (Smukler et al. 2006 ) experimenting at the edges of physiological con-
ditions, reported that mouse Embryonic Stem Cells (ESCs), when cultured in condi-
tions lacking instructive cues, start a neural differentiation program, suggesting that
this is the default pathway of early embryonic pluripotent cells. If that is the case,
signals from the organizer are important not in installing neural identity on stem
cells, but in liberating them form the activity of suppressors. Adding to the concept
of a mighty inherent programming in NSCs, both embryonic and adult-derived
NSCs can be cultured in vitro in very low densities (what is called clonal expansion)
where they exhibit the fundamental properties that are observed in the organism.
For example, in clones generated by embryonic cortical NSCs, neurons are gener-
ated before glial cells and with the appropriate temporal specification pattern
(Okano and Temple 2009 ). In addition, the decreased expression of a single gene
(encoding for the DNA-associated protein Trnp1) can produce gyrencephalia in the
normally lissencephalic (i.e. lacking cortical folds) mice (Stahl et al. 2013 ); whilst
over-expression only of Polo-like kinase 4 results in centrosome amplification in
NSCs and subsequent microcephaly (Marthiens et al. 2013 ). Furthermore, a Rho
E. Andreopoulou et al.