YSM Issue 86.4

BY SOMIN LEE
Imagine a production of all 38 of Shakespeare’s plays,
performed back-to-back, complete with over one
thousand characters and nearly a million words. The
success of the production depends critically on each
character saying the exact right words at the exact right
times. Although the flawless execution of such a play seems
daunting, the human brain orchestrates a similar task in the
formation of 100 trillion synapses between over 100 billion
neurons during development.
Synapses are the connections neurons use to communicate
with one another, and the proper creation and maintenance
of these connections are necessary for normal brain
function. Exactly how the brain manages such complexity
has been an interest of Professor Daniel Colón-Ramos of
the Yale School of Medicine for nearly a decade. As we
grow, our brains increase nearly fourfold in volume. The
mechanism behind the maintenance of synapses during such
dramatic growth is one of his lab’s primary interests. Current
research in his lab has now uncovered that the regulation
of a cell type called glia during growth may hold the key to
synapse regulation.
C. elegans as a Model Organism
Due to the overwhelming complexity of working with the
human brain, Colón-Ramos studies synaptic connections
in Caenorhabditis elegans (C. elegans), a small roundworm
about one millimeter in size. C. elegans is well-suited for
neurodevelopmental research in several ways. One major
advantage of C. elegans is the ease of genetic manipulation in
the species. Scientists in recent decades have also constructed
the entire C. elegans connectome, which means that we now
know the identity, morphology, and connectivity of each
of the 302 individual neurons in C. elegans. Colón-Ramos
described working with an organism with a completed
connectome as “a bit like having an answer key. We know
this is what a proper nervous system looks like so it’s much
easier to notice when things go wrong.”
Discovery of cima-1
The majority of synaptic connections form in the
embryonic stages, and these connections remain as the
animals grow into adults. To address the question of how
C. elegans maintains embryonically specified synapses, the
Colón-Ramos lab searched for genes involved in synapse
maintenance through a process known as forward genetics.
In the forward genetic approach, random mutations are
chemically induced in the DNA of the organism, creating C.
elegans with a wide array of abnormal features. These mutant
organisms are then screened for particular characteristics of
interest. To target genes involved in synapse maintenance,
the Colón-Ramos lab isolated mutants exhibiting normal
synapses as larvae but misaligned synapses as adults.
To uncover the exact genes and proteins malfunctioning
in the mutants, the lab conducted genetic fingerprinting on
the mutants’ DNA, a process similar to paternity tests in
humans. The test pointed to a mutation in a gene called cima-1
as the cause of the abnormal synaptic connections. Prior to
this study, cima-1 had never been investigated in C. elegans.
To further confirm that cima-1 acts critically during growth,
the lab created mutations in the cima-1 genes of abnormally
21 Yale Scientific Magazine | November 2013 www.yalescientific.org