Standing on their shoulders

I’ve been going through some older papers related to cortical development. These papers came out 10-15 years ago. I’ve never really appreciated older papers because they present outdated interpretations and techniques. I’m also wary of picking up interpretations that were later proven incorrect.
But after going through a series of related “older” papers, I’m really liking how the neuroscientists before me have tackled the mystery of cortex development. It’s pretty neat to see how an idea, which now the field takes for granted, was first proposed and experimentally tested, and then to see the same idea get revised and refined by studies using newer techniques. I feel like I’ve witnessed how a community of thinkers came together to our current knowledge of the origins of the cortex. It is even more exciting see myself as the continuation of this group effort. I have to stand on their past, mistakes and successes alike, to reach new intellectual frontiers.

August 4, 2014

Still considering how best to digest the primary literature in cerebral cortex development. Have finished reading some pretty informative review papers last week, will start going through their references now.

Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons
Zimmer et al., 2004
In the telencephalon Cux2 is expressed by two subpopulations that present different spatial origins, migratory behaviours and phenotypic characteristics: a subpopulation of cortical interneurons born in the subpallium, which migrates tangentially into the pallium and a subpopulation of cortical projection neurons born in the dorsal telencephalon. These cells seem to accumulate in the SVZ/IZ before their radial migration into superficial positions, where they differentiate into upper cortical layer neurons.
At E12.5 an early pool of dividing neuronal progenitors in the SVZ expresses Cux2. Moreover, the observation that Cux2+/PCNA+ as well as Cux2+/PHH3+ cells in the SVZ could be identified at later developmental stages (E14.5, E16.5) suggests that Cux2 is expressed by cells that divide in the SVZ throughout cortical development.
Cux2 expression is not linked to a maturation step of all cortical projection neurons, but identifies a subpopulation of projection neurons that is derived from the pallium.
Pax6 acts upstream of Cux2 and is specifically implicated in the determination of the UL fate, since DL seem to differentiate relatively normally.
DL and UL precursors might form two separate pools that arise from the same multipotent progenitor pool at around E10.5. Then, two populations are produced in the VZ: a post-mitotic population of DL neurons and a population of UL neuron precursors that divides in the SVZ (E12.5). These newly generated UL neurons migrate from the SVZ into the IZ, which shows the major increment in thickness in the mouse cortex at E14.5. Post-mitotic UL neurons may stay in this ‘sojourn zone’ for some time, until they receive the appropriate signal(s) to migrate radially through the CP and reach its outer most part (E16.5). The process of division of upper layer progenitors in the SVZ as well as their staging in the IZ appears to be continuous throughout corticogenesis (from E12.5 to E18.5) until the terminal differentiation of UL neurons (P14).
In humans and non-human primates, the early decrease of the VZ and the increase of the SVZ indicate that the latter is the major site of projection neuron production. Furthermore, in these species the pallial SVZ generates interneurons in addition to glial cells.
Cux2 seems to be an early molecular determinant of UL cortical neurons, potentially via a role in cell cycle regulation of intermediate progenitors in the SVZ.

Emx1 is a marker for most cells of the cerebral cortex in the process of proliferation, migration, and differentiation.
Mash1 knockout mice show a severe reduction of neuronal progenitors in the ventral telencephalon, and more specifically in the MGE.
Dlx5 is a marker for cortical interneurons.
ER81 is a marker for layer V neurons.
NeuN is a pan-neuronal marker.
Reeler is a mutant mouse strain in which the lack of the secreted molecule Reelin leads to severe alterations in cortical layering, namely an inversion of the normal ‘inside-out’ pattern.
PCNA is a cell cycle marker. It is mainly expressed from G1-phase through S-phase. It is used to determine if Cux2+ cells are dividing cells. The idea is that Cux2+/PCNA- cells are postmitotic interneurons, and Cux2+/PCNA+ cells are projection neurons.
PHH3 is another cell cycle marker. It is expressed mainly from late G2-phase through the M-phase of the cell cycle.
Sey mice, in which the mutation of the Pax6 gene has been suggested to induce a massive accumulation of UL neurons within the enlarged SVZ, while DL neurons appear to migrate relatively normally.

Thoughts:
Does CUX2 function in interneurons (deep layer) the same way it does in projection neurons (upper layer)? If not, then CUX2 would be an example of how nature efficiently employs the same molecule in different settings.
Is Cux2 controlled by different genetic programs in interneurons versus in projection neurons?
Can I get the upper-layer progenitors in mice to produce a greater variety of neurons, like they do in primates, once I figure out some of the key developmental programs at work?
Is there a connection between SVZ’s greater potential for generating projection neurons and its role in producing glia? Does glia production depend on projection neuron generation, or is it a separate developmental process that can be isolated? Is glia in the cortex important for higher cognitive function?
If upper-layer progenitors underwent further diversification in evolution to generate the majority of neuron subtypes in the cortex, I should expect to find many more molecular developmental controls in the upper-layer lineage than in the lower-layer lineage. I should also expect more neuron diversity in the upper layers than in the lower layers.

August 2, 2014

Origins of neocortical interneurons in mice
Welagen and Anderson, 2011
In mice, neocortical interneurons can be parsed into three nonoverlapping subgroups defined by the expression of parvalbumin, somatostatin, or vasoactive intestinal protein…These subgroups together comprise roughly 60% of neocortical interneurons. Additional subgroups, defined alone or in combination with other markers by the expression of calretinin, reelin, neuropeptide Y, and nitric oxide synthetase, comprise most of the remaining interneurons.

Thoughts:
The molecular characterization of cortical interneurons seems to be much more straight forward than that of cortical projection neurons. There are large, non-overlapping groups of interneurons marked by expression of one particular molecule.
It might be a good idea to use our definition of the different types of interneurons to help delineate projection neuron subtypes.