Presenilin-1 deficiency leads to loss of Cajal-Retzius neurons and cortical dysplasia similar to human type 2 lissencephaly.
BACKGROUND
Presenilin-1 (PS1) is a transmembrane protein that is located in the endoplasmic reticulum and the cis Golgi apparatus. Missense mutations of PS1 that modify gamma-secretase function, leading to a pathologic processing of amyloid precursor protein, are an important cause of familial Alzheimer's disease. Physiologically, the presenilins are involved in the Notch and Wnt-beta-catenin signaling pathways.


RESULTS
PS1-deficient mice develop a cortical dysplasia resembling human type 2 lissencephaly, with leptomeningeal fibrosis and migration of cortical-plate neurons beyond their normal position into the marginal zone and subarachnoid space. This disorder of neuronal migration is associated with the disappearance of the majority of the cells of the marginal zone, notably most of the Cajal-Retzius pioneer neurons, between embryonic days E14 and E18, and is preceded and accompanied by disorganization of Notch-1 immunoreactivity on the neuronal cell membranes. The marginal zone also becomes depleted of the extracellular matrix protein reelin and chondroitin sulfate proteoglycans. At that stage PS1 is transiently expressed in leptomeningeal fibroblasts, which are mandatory for the trophic support of Cajal-Retzius neurons.


CONCLUSIONS
In agreement with models in which neuronal migration disorders have been linked to a defect in Cajal-Retzius cells, the loss of most of these cells in PS1-deficient mice leads to cortical dysplasia. Because PS1 is normally expressed in the leptomeninges, and these become fibrotic in the PS1-knockout mice, we favor the hypothesis that the loss of Cajal-Retzius cells is caused by a defective trophic interaction with leptomeningeal cells, possibly involving disruption of Notch signaling.
Anatomisches Institut der CAU Kiel, Otto-Hahn-Platz 8, D-24 118, Kiel, Germany.
D
D
Hartmann
B
B
De Strooper
P
P
Saftig
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002465:Cell Movement; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000033:anatomy & histology / Q000098:blood supply / Q000196:embryology; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D008578:Meninges / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000502:physiology*; D053764:Presenilin-1; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D013997:Time Factors; D014157:Transcription Factors
D015816:Cell Adhesion Molecules, Neuronal; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; C497762:Notch1 protein, mouse; C508853:PSEN1 protein, human; D053764:Presenilin-1; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000091042:Reelin Protein; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse