Download Brain branches have Knots and Cuts

December 21, 2007
Brain branches have Knots and Cuts
RIKEN researchers elucidate mechanisms underlying brain connectivity
In the brain, innumerable cells reach out to one another in a seemingly chaotic tangle of
circuits and connections. Yet, hidden within this seeming chaos lie layers and patterns
of organization and order waiting to be deciphered. In a study published in the
December 20, 2007, issue of the journal Neuron, a team of researchers at the RIKEN
Brain Science Institute show how they have unraveled some of this apparent disorder
by illuminating how several molecular players work with and against each other to wire
certain parts of the brain.
One of the chief ways the 100 billion electrically excitable cells in our brain called
neurons interact and communicate with other neurons is by sending out tree-like,
branched extensions called dendrites - from 'dendron,' the Greek word for tree. The
dendrites of one neuron contact different parts of another neuron at junctions called
synapses. Any one neuron can be linked to as many as 10,000 other neurons, creating
a strikingly beautiful architectural symmetry of elaborately divided anatomical structures
called dendritic arbors.
No two human brains are alike because new connections, too many to count, are made
every second, changing the pattern and strength of various circuits. Healthy brain
function ultimately pivots around how efficiently information is transmitted, via synapses,
between neurons. The particular morphological arrangement of dendritic arbors in any
one neuron constitutes a 'computational signature' indicating the number and types of
input received by that neuron. This field is important in expanding our understanding of
brain function and the causes of neurological diseases in which there appears to be a
strong link between anomalous dendritic structure and disrupted neural function.
Dendritic arbors exhibit a great deal of structural plasticity, and their development
involves multiple steps controlled by both genetic and environmental drivers. To study
these molecular mechanisms the group worked with the humble fruit fly, Drosophila
melanogaster - a widely used research organism with a genome that overlaps
considerably with that of humans. Because the Drosophila brain is relatively accessible
and its genes easily manipulated, a great deal has been learned about complex brains
using this laboratory workhorse.
The RIKEN researchers examined a specific group of cells, called dendritic arborizaton
(da) neurons, which project dendrites only in two dimensions beneath the thin,
transparent body wall of Drosophila larva, and so are easily visualized, using special
fluorescent markers. The scientists worked on the premise that different types and
levels of special DNA-binding, gene expression-modulating proteins called transcription
factors work in concert to define different neurons. The group was particularly interested
in determining why increasing levels of one such transcription factor, Cut, corresponds
with increased dendritic outgrowth and complexity in all da classes except in class IV,
which has only moderate Cut levels but exhibits the most elaborate dendritic arbor
pattern.
The scientists discovered that this discrepancy was resolved by the fact that only class
IV da neurons express Knot, another transcription factor critical for arbor morphology.
Both Knot and Cut control distinct aspects of the dendritic cytoskeleton - the scaffolding
that is both the cell's 'muscle' and its 'skeleton.' The dynamics of Knot and Cut
interaction are complex: they control parallel pathways but they also work synergistically
and antagonistically to determine the final arbor architecture.
The researchers also demonstrated that Knot controls the expression of spastin, a
cytoskeletal building block regulator that is mutated in many patients suffering a disease
called autosomal dominant hereditary spastic paraplegia (AD-HSP). Based on their
finding that spastin is critical for complex arbor formation, the authors speculate that
AD-HSP pathology may involve defective dendritic development. Hence, this study
offers intriguing clues not only into how the brain works but also into how it may fail.
Original work:
Jinushi-Nakao, S., Arvind, R., Amikura, R., Kinameri, E., Liu, A., Moore, A.
Knot/Collier and Cut Control Different Aspects of Dendrite Cytoskeleton and Synergize
to Define Final Arbor Shape
Neuron, December 20, 2007
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