 |
The Journal of Neuroscience, December 26, 2007, 27(52):14459-14469; doi:10.1523/JNEUROSCI.4701-07.2007
Previous Article | Next Article 
Development/Plasticity/Repair
A Critical Function for β-Amyloid Precursor Protein in Neuronal Migration Revealed by In Utero RNA Interference
Tracy L. Young-Pearse,1
Jilin Bai,2
Rui Chang,1
Jessica B. Zheng,1
Joseph J. LoTurco,2 and
Dennis J. Selkoe1
1Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and 2Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut 06269
Correspondence should be addressed to Dennis J. Selkoe, Harvard Institutes of Medicine, Room 730, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: dselkoe{at}rics.bwh.harvard.edu
Physiological processing of the β-amyloid precursor protein (APP) generates amyloid β-protein, which can assemble into oligomers that mediate synaptic failure in Alzheimer's disease. Two decades of research have led to human trials of compounds that chronically target this processing, and yet the normal function of APP in vivo remains unclear. We used the method of in utero electroporation of shRNA constructs into the developing cortex to acutely knock down APP in rodents. This approach revealed that neuronal precursor cells in embryonic cortex require APP to migrate correctly into the nascent cortical plate. cDNAs encoding human APP or its homologues, amyloid precursor-like protein 1 (APLP1) or APLP2, fully rescued the shRNA-mediated migration defect. Analysis of an array of mutations and deletions in APP revealed that both the extracellular and cytoplasmic domains of APP are required for efficient rescue. Whereas knock-down of APP inhibited cortical plate entry, overexpression of APP caused accelerated migration of cells past the cortical plate boundary, confirming that normal APP levels are required for correct neuronal migration. In addition, we found that Disabled-1 (Dab1), an adaptor protein with a well established role in cortical cell migration, acts downstream of APP for this function in cortical plate entry. We conclude that full-length APP functions as an important factor for proper migration of neuronal precursors into the cortical plate during the development of the mammalian brain.
Key words: brain development; Alzheimer's disease; amyloid β-protein; neuronal migration; neural precursor; adhesion; integrins
Received Aug. 21, 2007;
accepted Nov. 12, 2007.
Correspondence should be addressed to Dennis J. Selkoe, Harvard Institutes of Medicine, Room 730, 77 Avenue Louis Pasteur, Boston, MA 02115. Email: dselkoe{at}rics.bwh.harvard.edu
Related articles in J. Neurosci.:
- This Week in The Journal
J. Neurosci. 2007 27: i.
[Full Text]
This article has been cited by other articles:

|
 |

|
 |
 
O. Reiner, A. Shmueli, and T. Sapir
Neuronal Migration and Neurodegeneration: 2 Sides of the Same Coin
Cereb Cortex,
July 1, 2009;
19(suppl_1):
i42 - i48.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. LoTurco, J.-B. Manent, and F. Sidiqi
New and Improved Tools for In Utero Electroporation Studies of Developing Cerebral Cortex
Cereb Cortex,
July 1, 2009;
19(suppl_1):
i120 - i125.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H.-S. Hoe, K. J. Lee, R. S. E. Carney, J. Lee, A. Markova, J.-Y. Lee, B. W. Howell, B. T. Hyman, D. T. S. Pak, G. Bu, et al.
Interaction of Reelin with Amyloid Precursor Protein Promotes Neurite Outgrowth
J. Neurosci.,
June 10, 2009;
29(23):
7459 - 7473.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Gralle, M. G. Botelho, and F. S. Wouters
Neuroprotective Secreted Amyloid Precursor Protein Acts by Disrupting Amyloid Precursor Protein Dimers
J. Biol. Chem.,
May 29, 2009;
284(22):
15016 - 15025.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Ishii and N. Maeda
Oversulfated Chondroitin Sulfate Plays Critical Roles in the Neuronal Migration in the Cerebral Cortex
J. Biol. Chem.,
November 21, 2008;
283(47):
32610 - 32620.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. Thinakaran and E. H. Koo
Amyloid Precursor Protein Trafficking, Processing, and Function
J. Biol. Chem.,
October 31, 2008;
283(44):
29615 - 29619.
[Abstract]
[Full Text]
[PDF]
|
 |
|
|

|