Dendrites, Filaments & Channels: Report from Neuroscience 2006
October 18th, 2006: Close to 25,000 neuroscientists convened in Atlanta, GA
this week for the Annual Meeting of the Society for Neuroscience. The
Foundation hosted the Research Information Booth, which attracted an
extensive amount of interest in our Young Investigator Award and Drug
Discovery Initiative programs.
A variety of presentations focused on neurofibromatosis, highlighted below.
One of the hottest areas of NF research in 2006 has been NF1-associated
learning disabilities, which has progressed rapidly from basic research into
Phase I clinical trials of Lovastatin. Children’s Tumor Foundation Young
Investigator Awardee Carrie Shilyansky, from the laboratory of Dr. Alcino Silva
(UCLA) provided an update on her research to unravel the functional &
molecular basis of prefrontal cortex deficits in NF1+/- mice. Carrie
demonstrated impaired response planning and increased prefrontal cortex
inhibition in these animals, with an increased frequency of GABAergic currents
in layer II/III pyramidal neurons and of smaller amplitude inhibitory currents.
Angy Kallarackal, a student from the laboratory of Dr. Aileen Bailey (University
of Maryland) reported on research to test a candidate therapeutic for learning
disabilities, namely Apamin. Angy’s research used the NF1 +/- mouse, which
exhibits learning disabilities that parallel the human, including visuospatial
defects. Previous studies by other investigators have demonstrated that human
NF1 -/- astrocytes have significant upregulation of small conductance calcium
activated potassium (SK) channels, which are principally located in the
neocortex & hippocampus. These channel deficits are also seen in the NF1 +/mouse. Angy’s research showed that apamin, which restores normal SK
channel function, improves learning deficits in NF1+/- mice.
Two related presentations presented research that is beginning to unravel how
the structure of neurons in the brain might impact on function as it relates to
learning. W. Zhang, from the laboratory of Dr. Luis Parada (University of
Texas, Southwestern) presented data showing that knockout of the
neurotrophin receptor TrkB; the tumor suppressor PTEN; or of the NF1 gene
each result in abnormal behavior of neuronal dendrite filopodia and synapse
formation in vitro. A common link is that all of these are dependent in normal
function on PI3 Kinase signaling. This is intriguing as defects in TrkB, PTEN and
NF1 function are all associated with impaired cognitive function: 60% of
children with NF1 develop learning disabilities, and this year Dr. Parada
reported that PTEN knockout in postmitotic neurons lead to an autism-like
phenotype in mice.
The finding that neurons are unable to form mature
dendritic & synaptic relationships when these genes are disrupted should help
understand the cellular & molecular basis of cognitive disorders in NF1 and
other disorders.
Intriguingly, PTEN, though traditionally viewed as a tumor suppressor, may
emerge to have a critical role in the early development of the brain on an
© 2006 Children’s Tumor Foundation
organization level, which subsequently impacts on function. In a ‘non-NF’ but
very intriguing presentation, Anthony Hill from the laboratory of Dr. Chris
Walsh (Beth Israel Deaconess Medical Center) reported on the effects on
cortical neuronal migration of conditional inactivation of PTEN under a nestin
promoter. Neurons in the cortex of these mice fail to migrate appropriately
and show abnormal axon bundling in the cortex. Importantly, the Cajal Retzius
cells and radial glia in the cortex – critical to normal neuronal migration &
layer formation – are poorly developed.
PTEN looks set to be recognized as a major player in normal brain development
& function; taken alongside the findings on NF1 and learning disabilities, we
are likely in the future to see major crossover roles for tumor suppressors in
normal brain function.
Jing Zhao from the laboratory of Dr. G. Wu (Baylor College of Medicine)
presented her findings from studies of NF1+/- hippocampal granule neurons in
vitro and in vivo. Jing also found that these neurons develop abnormal
dendrites and filopodia, and further demonstrated that these neurons have
elevates potassium flux. The emerging hypothesis from this research is that in
normal development, NF1 gene signaling is critical for dendritic formation &
development but that mature function requires a subsequent downregulation.
If this is lacking in NF1+/- and in the human disorder, it may be a key
contributor to learning deficits.
Finally on the learning disabilities theme, D.A. Kwasnicka-Crawford (York
University, Toronto) reported a finding from a patient of a novel chromosomal
mutation – a paracentric inversion - on Chromosome 3q25-29. The mutation was
inherited, and may be associated with language disorder. The affected gene
region appears to be adjacent to a gene encoding a novel schwannomin
(merlin) interacting protein, containing a calmodulin binding IQ motif. This
gene may be worth assessment as a candidate for developmental language
disorders.
NF tumor research & signaling pathway studies were also represented at the
meeting. Jon Williams, a student in the laboratory of Dr. Nancy Ratner
(University of Cincinnati) has identified a population of EGFR+ progenitor cells
that exist in normal peripheral nerve, and which is amplified in NF1 mutant
mice. These cells could represent a miscreant subpopulation that contributes
to tumor formation in NF1 peripheral nerves, and presents a rational for
therapeutic targeting of EGFR in NF1.
Dr. Mimika Mangoura (Academy of Athens) presented data on the study of
embryonic stem (ES) cell differentiation into neurons. The work showed that
neurofibromin and protein kinase C expression as being interdependent during
normal neuronal differentiation, and also showed that the two are functionally
coupled with neurofibromin phosphorylation being a critical event. In NF1
tumors a subpopulation of astrocytes are neoplastic, with enhanced
proliferation & motility. Danielle Scheidenhelm, a student from the laboratory
© 2006 Children’s Tumor Foundation
of Dr. David Gutmann (Washington University, St. Louis, MO) presented her
work on unraveling the role of mTOR in these cells. The mTOR pathway is
hyperactive in reactive NF1 -/- astrocytes. These cells lose the organized array
of actin stress fibers that is characteristic of normal astrocytes. Danielle’s
research has shown that this is mTOR mediated since treatment of NF1 -/astrocytes with rapamycin, or genetic rescue of these cells, restores normal
patterns of actin filaments. Danielle is now looking for effectors even further
downstream, for specific mediators of both motility & proliferation in NF1 -/astrocytes. As well as unraveling the molecular & cellular basis of the NF1-/astrocyte phenotype, this research could lead to the identification of future
drug targets for the treatment of NF1 tumors.
Pain is a feature of NF that is not well studied. Y. Wang (Indiana University)
reported that NF1+/- mouse sensory neurons have enhanced excitability, in
part due to augmented sodium currents. This could contribute functionally to
abnormal function including enhanced pain in NF1.
Finally in an intriguing poster, Y. Hitoshi (Dartmouth Medical School) reported
what could be new mouse models for the study of NF1 or NF2. The mouse
models overexpress PDGF-B, under promoters GFAP or tetracycline-regulated
promotor. Both mouse models developed NF-like tumors throughout a number
of peripheral nerves notably at the spinal roots. Dr. Hitoshi will be doing
further cellular & molecular analysis of the tumors that develop in these mice
to fully assess their utility in studying NF.
© 2006 Children’s Tumor Foundation