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My laboratory is
interested in elucidating the mechanism by which neurotrophins regulate the
formation, maintenance, and function of neural circuits in the brain.
Deficiencies in neurotrophins have been linked to neurodegenerative diseases,
mental retardation, obesity, and other neurological disorders. Neurotrophins are
a family of small and secreted growth factors, which include brain-derived
neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3, and
neurotrophin-4/5. My laboratory uses a combination of mouse genetic,
biochemical, molecular, histological, and behavioral approaches to identify the
neural and molecular bases mediating the diverse functions of neurotrophins. We
have found that BDNF synthesized in dendrites controls activity-dependent
modifications of dendritic spines that are the sites of contact for excitatory
synapses. We also found that neurotrophins are required for the formation and
maintenance of the striatum. Their deficiencies likely contribute to selective
degeneration of striatal neurons in Huntington’s disease. Much of the current
work in the laboratory is focused on the regulation of local BDNF synthesis and
its role in synaptic plasticity, the molecular mechanism underlying the
development and maintenance of the striatum and its relevance to Huntington’s
disease, the molecular and neural bases underlying the effect of BDNF on body
weight, and the molecular mechanism of retrograde neurotrophic signaling.
1.
Regulation of synaptic plasticity and learning by dendritic local protein
synthesis: BDNF has
been shown to be a powerful regulator of synaptic plasticity. Our recent
findings indicate that dendritically synthesized BDNF plays a vital role in
activity-dependent synaptic modifications. We are interested in how activity
controls the transport of mRNAs for BDNF and its receptor TrkB to dendrites and
the translation of dendritically localized BDNF and TrkB mRNAs, how locally
synthesized BDNF and TrkB proteins are secreted or inserted into the cell
membrane in dendrites that contain few Golgi-like organelles, and how locally
synthesized BDNF and TrkB regulate synaptic structures. We also investigate
whether down- or up-regulation of local synthesis of BDNF or TrkB affects animal
behaviors, including learning and memory, locomotion, eating, and mood. Since
our previous findings show that mice deficient in local BDNF synthesis have
spine phenotypes similar to what found in patients with mental retardation, one
study is to examine whether deficits in local BDNF synthesis contribute to the
pathogenesis of fragile X syndrome, the most common hereditary mental
retardation disorder.
2.
Role of neurotrophins in striatal neurons and its relevance to Huntington’s
disease: The
striatum is the largest structure of the basal ganglia and its malfunction has
been linked to Parkinson’s disease, Huntington’s disease, schizophrenia, and
other neurological disorders. We investigate the role of neurotrophins in the
development and survival of striatal neurons and synaptic plasticity at the
corticostriatal synapse by selectively deleting the genes for neurotrophins and
their receptors in these neurons. Striatal levels of BDNF have been found to be
reduced in patients and mice with Huntington’s disease, which is characterized
by selective degeneration of one subset of striatal projection neurons. Our
recent findings indicate the deficiency in striatal BDNF supply contributes to
the pathogenesis of Huntington’s disease. We currently examine whether the BDNF
deficiency leads to the selective neurodegeneration in Huntington’s disease.
3. The
neural and molecular mechanisms through which BDNF controls body weight: A
reduction in expression of either BDNF or TrkB leads to severe obesity in both
mice and human. Our previous findings indicate that BDNF synthesized in the
ventromedial hypothalamus (VMH) plays a crucial role in the control of body
weight. Several ongoing projects aim to link BDNF to the established
appetite-controlling pathways, to identify the neural circuit through which BDNF
regulates appetite, and to understand how BDNF regulates the function of the
circuit.
4.
Role of a novel zinc finger protein in retrograde neurotrophic signaling:
Many
neurons (e.g. motor neurons and sensory neurons) innervate a target far away
from their cell bodies. Their development, function, and survival depend on
target-derived growth factors. It is an important neurobiology topic to
understand how target-derived growth factors retrogradely transmit their signals
from axonal terminals to cell bodies over a long distance. We have identified a
novel protein that interacts with neurotrophin receptors and is required for
retrograde neurotrophic signaling. We employ
compartmentalized neuronal cultures and other techniques to elucidate the
mechanism by which this novel protein is involved in this retrograde signaling
process.
Selected Publications:
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Waterhouse
EG, Xu B.:
New insights into the role of brain-derived neurotrophic factor in synaptic
plasticity.
Mol
Cell Neurosci., 2009
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An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F,
Torre ER, Jones KR, Feng Y, Lu B, Xu B.:
Distinct role of long 3' UTR BDNF mRNA in spine morphology and synaptic
plasticity in hippocampal neurons.
Cell. 134:175-87, 2008
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Liao GY, Xu B.:
Cre recombinase-mediated gene deletion in layer 4 of murine sensory cortical
areas.
Genesis. 46:289-93, 2008
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Grishanin RN, Yang H, Liu X, Donohue-Rolfe K, Nune GC,
Zang K, Xu B, Duncan JL, Lavail MM, Copenhagen DR, Reichardt LF.:
Retinal TrkB receptors regulate neural development in the inner, but not
outer, retina.
Mol Cell Neurosci. 38:431-43, 2008
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Gharami K, Xie Y, An JJ, Tonegawa S, Xu B.:
Brain-derived neurotrophic factor over-expression in the forebrain
ameliorates Huntington's disease phenotypes in mice.
J Neurochem. 105:369-79, 2008
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Liu X, Grishanin RN, Tolwani RJ, Rentería RC, Xu B,
Reichardt LF, Copenhagen DR.:
Brain-derived neurotrophic factor and TrkB modulate visual
experience-dependent refinement of neuronal pathways in retina.
J Neurosci. 27:7256-67, 2007
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Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM,
Pierri JN, Sun Z, Sampson AR, Lewis DA.:
Relationship of brain-derived neurotrophic factor and its receptor TrkB to
altered inhibitory prefrontal circuitry in schizophrenia.
J Neurosci.
25:372-83, 2005
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Paredes A, Romero C, Dissen GA, DeChiara TM, Reichardt L,
Cornea A, Ojeda SR, Xu B.:
TrkB receptors are required for follicular growth and oocyte survival in the
mammalian ovary.
Dev Biol. 267:430-49, 2004
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Xu B, Goulding EH, Zang K, Cepoi D, Cone RD, Jones KR,
Tecott LH, Reichardt LF.:
Brain-derived neurotrophic factor regulates energy balance downstream of
melanocortin-4 receptor.
Nat Neurosci. 6:736-42, 2003
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Tran PV, Lee MB, Marín O, Xu B, Jones KR, Reichardt LF,
Rubenstein JR, Ingraham HA.:
Requirement of the orphan nuclear receptor SF-1 in terminal differentiation
of ventromedial hypothalamic neurons.
Mol Cell Neurosci. 22:441-53, 2003
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Rico B, Xu B, Reichardt LF.:
TrkB receptor signaling is required for establishment of GABAergic synapses
in the cerebellum.
Nat Neurosci. 5:225-33, 2002
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