Gene Targeting of CRMP-1 in Mice as a Model For Brain Functional Study
Date Issued
2007
Date
2007
Author(s)
Su, Kang-Yi
DOI
zh-TW
Abstract
Brain function needs the precise anatomical and histological connections generated by exquisitely specific axonal guidance system during development. Neuronal outgrowth is directed by attracting by attracting and repelling signaling molecules. Well known guidance cues are semaphorins/collapsins. Semaphorin 3A, also known as Collapsin-1 is thought to be an initiator of signaling involved in neural growth cone outgrowth. Collapsin response mediator proteins (CRMPs) are a family of cytosolic phosphoproteins that mediate the signal from Semaphorin 3A. Collapsing response mediator protein-1 (CRMP-1) was initially identified in brain and has been implicated in plexin-dependent neuronal function. The high amino acid sequence identity among the five CRMPs has hindered determination of the functions of each individual CRMP. In 2001, CRMP-1 had also been characterized as a tumor metastasis suppressor gene dependent on its role in lung cancer metastasis and clinical outcome. In order to study the physiological function of CRMP-1 in vivo, we generated viable and fertile CRMP-1 knockout (CRMP-1-/-) mice with no evidence of gross abnormality in the major organs and difference in hematological and biochemical analysis between wild-type mice. According to high CRMP-1 expression in the hippocampus, we analyzed the formation of axon and dendrite there by staining with neural markers. CRMP-1-/- mice exhibited intense MAP2 staining in the proximal portion of the dendrites, but reduced and disorganized MAP2 staining in the distal dendrites of hippocampal CA1 pyramidal cells. Immunoreactivity to GAP-43 and PSD95 (a postsynaptic membrane adherent cytoskeletal protein) was also decreased in the CA1 region of the knockout mice. These changes were consistent with the mutant mice showing a reduction in long-term potentiation (LTP) in the CA1 region and impaired performance in hippocampal-dependent spatial learning and memory tests. CRMP-1-/- mice showed a normal synapsin I labeling pattern in CA1 and normal paired pulse facilitation. In addition, CRMP-1-/- also showed more depressed in forced swimming test suggested that CRMP-1 may involved in emotion control. These findings provide the first evidence suggesting that CRMP-1 may be involved in proper neurite outgrowth in the adult hippocampus and that loss of CRMP-1 may affect LTP maintenance and spatial learning and memory. Furthermore, CRMP-1-/- mice also exhibit more depressed in forced swimming test compared with wild-type mice suggested that CRMP-1 may regulate emotion response. On the other hand, CRMP-1-/- mice also show defect in cerebellum development. Mice deficient in CRMP-1 not only showed reduced weight in cerebellum but also lack the normal organic structure in VIb lobe suggested that CRMP-1 also involved in cerebellum development.
Subjects
CRMP-1
基因剔除
海馬迴
軸突形成
長效性電位
空間學習記憶
gene targeting
cre-loxP
hippocampus
axon guidance
apical dendrite formation
long-term potentiation
Morris Water Maze
learning and memory
SDGs
Type
other
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