Chronicles of a Graduate Student Let Loose in Europe (Part 1)

Georgia Panagiotakos is a senior graduate student in the labs of Drs. Ricardo Dolmestch and Theo Palmer, where she studies mechanisms by which mutations in the voltage gated calcium channel CaV1.2 influence neurogenesis in the developing brain and contribute to the pathophysiology of autism spectrum disorders. The spring/summer Georgia attended two scientific conferences in Europe, and graciously volunteered to write a two-part blog post chronicling her experiences. This past month has marked the first time in my graduate career that I have had the opportunity to travel overseas for a scientific meeting and interact with giants in my field. In a stroke of remarkable luck, I was able to attend two different conferences, both of which took place in Europe. The first of these was small and specialized, an assortment of about two hundred scientists from around the world focused exclusively on understanding the mechanisms underlying brain development and the evolution of the human cortex (ed. note: the conference is question is entitled Cortical Development: Neural Stem Cells to Neural Circuits). The second meeting was quite broad, bringing together students and postdocs from over eighty countries to interact with twenty-six Nobel laureates in medicine and physiology (ed. note: this is the Lindau Nobel Laureate Meeting).

Admittedly, I approached this second meeting with some nerves (How difficult would it be to really have a stimulating scientific discussion with someone whose research interests are so distant from mine? Could I really convey the excitement I feel about what I do and the importance of neuroscience research to someone focused on understanding the structure of a protein or examining the life cycle of a virus?) - these fears proved to be moderately irrational and this experience was one that I will never forget. In telling some friends about these two wonderful experiences, I was prompted to transcribe some of what I heard into my first (and likely last) entry on the Stanford neuroblog. I needed a little pick-me-up today, so what follows is a pleasant distraction, a short description of each meeting, interspersed with a series of memorable quotes.

Surprisingly (read: not at all surprisingly), it appears that I am incapable of writing something “short”. I hope that this entry is sufficiently interesting to you to allow me some liberty with words.

During the third week of May, I flew to Greece (my homeland - conference for the win!) to attend a meeting on cortical development. I suppose I should preface everything I write here with the statement that I have been intrigued by cortical development, and how it is that specific cell types are generated and functionally connected in the developing brain, for about as long as I have been interested in neuroscience. This really reflects itself in the fact that a significant portion of my scientific career to date (young as it is) has centered around aspects of this very broad question. In light of this, the opportunity to attend this meeting was really a remarkable treat. An additional disclaimer: It didn’t hurt that the meeting was to take place on the island of Crete. And I cannot say that we didn’t take advantage of the beautiful weather and majestic Mediterranean sea - but the meeting itself proved to be on par with the exceptional location. Over the course of four days, we heard from the likes of Arnold Kriegstein, Pasko Rakic, Gord Fishell, Jeff Macklis, Arturo Alvarez-Buylla, Chris Walsh, and others, in sessions focused on stem cells, neurogenesis and neuronal differentiation, neuronal migration, circuit formation and neuronal circuits. I decided not to detail every talk here, in the interest of time (both mine and yours), and to focus instead on my impressions from the meeting now that I’ve had several weeks to ruminate.

Two over-arching themes that seem to be driving the field of cortical development really popped out for me at this meeting:

Neuronal subtype specification.

In particular, many of the talks centered around understanding the development, migration and maturation of cortical interneurons and exploring their role in sculpting cortical circuit function (a long standing interest of mine that I like to think of as a guilty pleasure of sorts). The conclusion of the series of talks surrounding this question requires me to, if I may, borrow a phrase that Jeff Macklis used during his excellent talk describing the acquisition of neocortical projection neuron identity - a “combinatorial multi-state logic” in the form of the activation or repression of specific transcription factors at different stages of development, responsiveness to guidance molecules, feedback mechanisms and neuronal activity (as beautifully depicted in a recent paper from the lab of Gord Fishell) is employed by the developing brain to generate remarkably diverse populations of interneurons that terminate in specific locations, exhibit different physiological properties and integrate into specific cortical circuits. Interesting to think about is how these strategies are integrated by individual cells as they mature and acquire their terminal fates.

Evolution of the human cortex.

The other point of emphasis at this meeting was the development of hypotheses regarding the evolution of the human cortex, in particular the expansion of the upper layers and the diversification of neuronal populations. A significant proportion of speakers, whether they were studying interactions of neural progenitor cells with the extracellular matrix, or basic mechanisms of cell division, or human-specific disease mutations, at the very least commented on how their finding might impact our understanding of human brain evolution. Arnold Kriegstein started the meeting off by presenting his beautiful work describing the behavior of outer radial glial cells, a new class of neural progenitor cell located in a separate anatomical zone in the developing monkey and human brain termed the outer subventricular zone (oSVZ). He showed us the elegant time-lapse images for which he is famous, depicting these cells translocating their somata (literally “jumping”) and subsequently dividing to give rise to daughter cells by undergoing characteristic modes of cell division. The massive expansion of the oSVZ during mid-gestation in humans prompted Kriegstein to argue the importance of these outer radial glial cells for the expansion of the human neocortex, through an increase in the number of neurons being generated. He further suggested that these different progenitor niches in the developing brain might allow for the emergence of heterogeneous cell types even at the same birthdate. That same afternoon, we heard Pasko Rakic (in a session chaired by Kriegstein himself) assert that the oSVZ is not the most important feature for the evolution of the cortex. Gauntlet thrown? We later heard from Chris Walsh, who described another approach at uncovering important players in human cortical development, the use of Next-Gen sequencing to identify disease mutations that cause cortical malformations. He went on to talk about a separate project in his lab that focused on the role secreted factors in the cerebrospinal fluid might play in instructing cell fate decisions and proliferation in the developing brain.

The meeting closed with what admittedly may have been one of my favorite talks, a beautiful story by Nenad Sestan describing the patterning of microcolumns in the developing human cortex and efforts towards completing a developing human brain transcriptome. I would be remiss if I didn’t also give a shout out to my friend and fellow Stanford neuroscience program graduate student, Alex Pollen, who (for once not talking about penile spines!) presented a wonderful poster describing his work aimed at identifying human-specific deletions of regulatory elements that may underly the evolution of human-specific brain features. Overall, I was left with the impression of a vibrant field in which a number of labs are using very different approaches to unravel the mechanisms underlying human-specific cortical expansion. It’s only fitting that I close this part with a quote from the man himself, Pasko Rakic: “It’s more complicated than I say, but they only gave me forty minutes.”