Strieder Essay 1
Some Thoughts on "Naturalization"
and Morphological Homology
When cells migrate from a subpallial germinal zone into
the dorsal pallium, does that mean that the dorsal pallium is partly subpallial?
More generally, when an adult cell group is derived from several different
precursor zones, how does that influence our thoughts about its homology?
We usually take the site of a structures developmental origin as
a strong indicator of its homology (i.e., structures that resemble each
other in terms of where they develop from are probably homologous to one
another), but what do we do when an adult structure comes from several
different precursor regions? I was discussing these questions with Laura
Bruce and Loreta Medina late one night in Murcia, towards the end of a
big meeting there, when Loreta drew an interesting analogy. She suggested
that the GABAergic cells that migrate from the subpallial ventricular
zone into the dorsal pallium might be considered as "naturalized
immigrants" into the dorsal pallium. Being a naturalized U.S. citizen,
I think I understood what she meant (but, as they say, dont blame
her for anything I write). Since then, I have thought some more about
this and found it to be a rather complex, but still fruitful, analogy.
Although I have not come to any firm conclusions, I thought Id share
my thoughts with you. Perhaps collectively we can sort it all out.
As I see it, naturalized citizens are fully integrated
into their adopted (adoptive?) country but need not drop all of their
native cultural heritage. To become a naturalized citizen of the US, for
example, you must speak a minimum amount of English, know something about
the history and governance of the US, and repudiate your allegiance to
"any foreign prince or potentate". You need not, however, become
an "average citizen". They used to talk about America being
a "melting pot" but I think it is really more like a stew, composed
of many different chunks that all contribute to the overall flavor yet
retain some identity. Naturalized immigrants may imbibe a great deal of
"mass culture" (e.g. TV) but still hang out with their "own
kind", practice a different religion, eat different (ethnic")
foods, or buy a satellite dish to watch foreign channels. In other words,
cultural integration comes in many different forms and can vary in extent.
Naturalization has relatively little to do with how much of the native
identity has been surrendered.
So, assuming Ive got this right, lets examine
how the naturalized immigrant analogy might apply to brains, and lets
consider first the cells that emigrate from the subpallium into the dorsal
pallium (neocortex in mammals) where they ultimately become GABAergic
interneurons. These immigrant neurons are integrated with their native
neighbors in the sense that they interconnect with other dorsal pallial
neurons, but this is a relatively weak form of integration (perhaps analogous
to the communication between tourists and native residents). Better evidence
for "full integration" would be to show that the immigrant cells
are induced to express some genes that they would not have expressed had
they "stayed home". To my knowledge, we do not know how the
development of the GABAergic immigrants is influenced by their "host
region" (I suspect people are working on this). Until we have such
evidence, it is difficult to know how "fully integrated" the
cellular immigrants are. Even less clear would be the point at which these
immigrants would earn the appellation "naturalized immigrants".
One might call the immigrants "naturalized" if they "vote"
together with the other cells in some computational sense, but what precisely
that would mean is unclear. Thus, it is possible to make the analogy work
in this case, but proving developmental integration is difficult and the
naturalization criteria are rather arbitrary.
Now let us consider another case, where the degree of immigrant
integration is likely to be even lower. As I understand it, David Perkel,
Tony Reiner, Sarah Bottjer and others have collectively shown that some
neurons in the avian area X resemble those of the mammalian striatum,
while others in the same area bear a striking resemblance (in terms of
physiological properties and histochemistry) to cells in the mammalian
globus pallidus. This suggests that perhaps there has been some developmental
intermingling of cells (though this is not the only imaginable explanation)
to create area X but that the different immigrant cell populations have
retained much of their native characteristics. To really show this, of
course, one would have to conduct experiments. But let us assume for the
moment that area X really forms by the developmental intermingling of
"striatal" and "pallidal" cell populations. Which
population should be considered "naturalized immigrants" and
which should be considered to provide area X with its "national identity"?
Should it be a majority decision? Before you say yes, consider that many
countries are dominated (both culturally and militarily) by a minority
of their population. Should national identity be decided by the cells
that reached their ultimate target via the shortest route (e.g. by radial
rather than tangential migration)?
Proceeding to even more extreme examples, consider the
case of microglia. As I understand it (from textbooks, admittedly), microglia
probably invade the brain during development and thus become, essentially,
the brains resident macrophages. In a sense, they are "permanent
residents", doing some of the work that the other glia are either
unwilling or unable to do (I suppose my pro-immigrant bias is showing
here). If this is correct, should we consider the microglia to be naturalized
citizens of whatever brain area they are in? Or should we specifically
exclude the microglia when we talk about a particular brain area in homology
comparisons? Similarly, we know from Drew Nodens work that the endothelial
cells lining the brains blood vessels are derived from mesoderm
rather than neurectoderm (which gives rise to the neurons and most of
the glia). Functionally, the endothelial cells are certainly integrated
rather tightly with the neurons that are nearby (just imagine what would
happen to those neurons if there were no endothelial cells), but does
that mean they are naturalized citizens of the brain? Or have we crossed
a line into fruitless mental exercises?
I dont know, but I come away from these musings with
the following tentative resolutions. One, where cells come from in terms
of lineage is less important than how tightly they are integrated with
other cells. Two, functional integration (e.g. synaptic communication)
is less important for "naturalization" than developmental integration
(i.e. being developmentally influenced by your neighbors). Three, to think
clearly about this issue, it is necessary to distinguish between homologies
(or identities) at the cellular and aggregate levels of analyses (e.g.
aggregates may be homologous as aggregates, even though not all of their
constituent cell populations are homologous as cell populations). Four,
none of this may matter all that much for homology comparisons unless
there are significant differences in developmental origin and/or cell
composition between similar structures in different species (e.g. the
dorsal pallium may receive subpallial immigrants in most species, as Luis
Puelles has suggested; but note that Rakic and his collaborators have
shown that humans differ from other species in having telencephalic cells
contribute to part of the dorsal thalamus). Five, in the few cases where
these issues become important (where there are significant differences
between species), some arbitrariness tends to creep in (i.e. we humans
will be tempted to decide by committee or ex cathedra which cell population
is immigrant and which is native, and how much developmental integration
is sufficient to consider the immigrants naturalized).
Of these conclusions, only the fifth one bothers me because
I like to think that structural identity and homology are not simply constructs
that we impose (arbitrarily) on nature. The dividing line between a limb
and a trunk may be arbitrary to some extent, but I think limbs and trunks
are nonetheless distinct entities, independently of whoever is arguing
about them. Similarly, I hope that the dorsal pallium is an entity independently
of whatever a committee of scientists decides are its critical features
(or its identity-conferring cells). Perhaps I am philosophizing excessively,
but to me this issue is important, and I think it can be resolved. For
me, resolution lies in the observation that there are (seem to be?) such
things as developmental units, or modules, that develop largely independently
of one another. When these modules form, they work with whatever materials
they can use, much as a whirlpool incorporates whatever water molecules
(or swimmers) it can pull in. From this perspective (which I would call
a "dynamic systems" perspective), the "immigrants"
I talked about before might be the leaves that fell into river but are
sucked into the whirlpool just like the water is. The leaves become part
of the whirlpool (i.e. naturalized if you will) as soon as they become
part of the overall whirlpool pattern. Returning to neurobiology, I think
that the major challenge for neurobiologists is to figure out what kind
of dynamic patterns are involved in creating particular brain areas (e.g.
the dorsal pallium) and how any immigrant cell populations are integrated
into those processes.
In sum, I think that the term "naturalization"
can be used to denote cells that become developmentally integrated with
other cells in a distant brain region. In contrast, non-naturalized immigrants
do not interact developmentally with their "host" cells, which
means that the resultant adult structure is heterogeneous or "composite".
I know that the issues I have discussed here don't bear
on the question of how to name various telencephalic areas in any obvious
way, but I think they are relevant to some of the deeper issues that are
at stake and bound to come up. I hope my musings are helpful at least
insofar as they stimulate thought.
Acknowledgements: Thanks to Loreta Medina and David Perkel for feedback.
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