Neurogenic phenotypes and altered Notch processing in Drosophila Presenilin mutants

被引:443
作者
Ye, YH [1 ]
Lukinova, N [1 ]
Fortini, ME [1 ]
机构
[1] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
关键词
D O I
10.1038/19096
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Presenilin proteins have been implicated both in developmental signalling by the cell-surface protein Notch and in the pathogenesis of Alzheimer's disease. Loss of presenilin function leads to Notch/lin-12-like mutant phenotypes in Caenorhabditis elegans(1,2) and to reduced Notch1 expression in the mouse paraxial mesoderm(3). In humans, presenilins that are associated with Alzheimer's disease stimulate overproduction of the neurotoxic 42-amino-acid beta-amyloid derivative (A beta 42) of the amyloid-precursor protein APP(4). Here we describe loss-of-function mutations in the Drosophila Presenilin gene that cause lethal Notch-like phenotypes such as maternal neurogenic effects during embryogenesis, loss of lateral inhibition within proneural cell dusters, and absence of wing margin formation. We show that presenilin is required for the normal proteolytic production of carboxy-terminal Notch fragments that are needed for receptor maturation and signalling, and that genetically it acts upstream of both the membrane-bound form and the activated nuclear form of Notch. Our findings provide evidence for the existence of distinct processing sites or modifications in the extracellular domain of Notch. They also link the role of presenilin in Notch signalling to its effect on amyloid production in Alzheimer's disease.
引用
收藏
页码:525 / 529
页数:5
相关论文
共 30 条
[1]   Intracellular cleavage of notch leads to a heterodimeric receptor on the plasma membrane [J].
Blaumueller, CM ;
Qi, HL ;
Zagouras, P ;
ArtavanisTsakonas, S .
CELL, 1997, 90 (02) :281-291
[2]   Roles for proteolysis and trafficking in notch maturation and signal transduction [J].
Chan, YM ;
Jan, YN .
CELL, 1998, 94 (04) :423-426
[3]   Serrate and wingless cooperate to induce vestigial gene expression and wing formation in Drosophila [J].
Couso, JP ;
Knust, E ;
Arias, AM .
CURRENT BIOLOGY, 1995, 5 (12) :1437-1448
[4]   PRONEURAL CLUSTERS OF ACHAETE-SCUTE EXPRESSION AND THE GENERATION OF SENSORY ORGANS IN THE DROSOPHILA IMAGINAL WING DISK [J].
CUBAS, P ;
DECELIS, JF ;
CAMPUZANO, S ;
MODOLELL, J .
GENES & DEVELOPMENT, 1991, 5 (06) :996-1008
[5]   Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein [J].
De Strooper, B ;
Saftig, P ;
Craessaerts, K ;
Vanderstichele, H ;
Guhde, G ;
Annaert, W ;
Von Figura, K ;
Van Leuven, F .
NATURE, 1998, 391 (6665) :387-390
[6]  
DiazBenjumea FJ, 1995, DEVELOPMENT, V121, P4215
[7]  
Dietrich U, 1984, J Neurogenet, V1, P315, DOI 10.3109/01677068409107094
[8]   COMPLEX CELLULAR AND SUBCELLULAR REGULATION OF NOTCH EXPRESSION DURING EMBRYONIC AND IMAGINAL DEVELOPMENT OF DROSOPHILA - IMPLICATIONS FOR NOTCH FUNCTION [J].
FEHON, RG ;
JOHANSEN, K ;
REBAY, I ;
ARTAVANISTSAKONAS, S .
JOURNAL OF CELL BIOLOGY, 1991, 113 (03) :657-669
[9]   MOLECULAR-INTERACTIONS BETWEEN THE PROTEIN PRODUCTS OF THE NEUROGENIC LOCI NOTCH AND DELTA, 2 EGF-HOMOLOGOUS GENES IN DROSOPHILA [J].
FEHON, RG ;
KOOH, PJ ;
REBAY, I ;
REGAN, CL ;
XU, T ;
MUSKAVITCH, MAT ;
ARTAVANISTSAKONAS, S .
CELL, 1990, 61 (03) :523-534
[10]   THE SUPPRESSOR OF HAIRLESS PROTEIN PARTICIPATES IN NOTCH RECEPTOR SIGNALING [J].
FORTINI, ME ;
ARTAVANISTSAKONAS, S .
CELL, 1994, 79 (02) :273-282