The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons

O. Berezovska, M. Frosch, Pamela J McLean, R. Knowles, E. Koo, D. Kang, J. Shen, F. M. Lu, S. E. Lux, S. Tonegawa, B. T. Hyman

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin-12, Notch1, is a transmembrane receptor that plays an important role in cell fate decisions during development, including neurogenesis, but does not have a known function in fully differentiated cells. To better understand the potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 transfection on neurite outgrowth in primary cultures of hippocampal/cortical neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furthermore, we present evidence demonstrating that there is a functional interaction between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin-12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibitory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overexpressing wild type PS1, but not mutant PS1. These data suggest that PS1 facilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons. Copyright (C) 1999 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)273-280
Number of pages8
JournalMolecular Brain Research
Volume69
Issue number2
DOIs
StatePublished - 1999
Externally publishedYes

Fingerprint

Presenilin-1
Caenorhabditis elegans
Neurons
Presenilins
Genes
Alzheimer Disease
Neurobiology
Neurogenesis
Neurites
Knockout Mice
Transgenic Mice
Transfection

Keywords

  • Notch1
  • Presenilin 1
  • Primary neurons
  • PS1 knockout mice
  • PS1 transgenics

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons. / Berezovska, O.; Frosch, M.; McLean, Pamela J; Knowles, R.; Koo, E.; Kang, D.; Shen, J.; Lu, F. M.; Lux, S. E.; Tonegawa, S.; Hyman, B. T.

In: Molecular Brain Research, Vol. 69, No. 2, 1999, p. 273-280.

Research output: Contribution to journalArticle

Berezovska, O, Frosch, M, McLean, PJ, Knowles, R, Koo, E, Kang, D, Shen, J, Lu, FM, Lux, SE, Tonegawa, S & Hyman, BT 1999, 'The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons', Molecular Brain Research, vol. 69, no. 2, pp. 273-280. https://doi.org/10.1016/S0169-328X(99)00119-9
Berezovska, O. ; Frosch, M. ; McLean, Pamela J ; Knowles, R. ; Koo, E. ; Kang, D. ; Shen, J. ; Lu, F. M. ; Lux, S. E. ; Tonegawa, S. ; Hyman, B. T. / The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons. In: Molecular Brain Research. 1999 ; Vol. 69, No. 2. pp. 273-280.
@article{23a29174b7dc4daa8f4a83ac025bcfb8,
title = "The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons",
abstract = "The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin-12, Notch1, is a transmembrane receptor that plays an important role in cell fate decisions during development, including neurogenesis, but does not have a known function in fully differentiated cells. To better understand the potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 transfection on neurite outgrowth in primary cultures of hippocampal/cortical neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furthermore, we present evidence demonstrating that there is a functional interaction between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin-12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibitory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overexpressing wild type PS1, but not mutant PS1. These data suggest that PS1 facilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons. Copyright (C) 1999 Elsevier Science B.V.",
keywords = "Notch1, Presenilin 1, Primary neurons, PS1 knockout mice, PS1 transgenics",
author = "O. Berezovska and M. Frosch and McLean, {Pamela J} and R. Knowles and E. Koo and D. Kang and J. Shen and Lu, {F. M.} and Lux, {S. E.} and S. Tonegawa and Hyman, {B. T.}",
year = "1999",
doi = "10.1016/S0169-328X(99)00119-9",
language = "English (US)",
volume = "69",
pages = "273--280",
journal = "Brain Research",
issn = "0006-8993",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - The Alzheimer-related gene presenilin 1 facilitates notch 1 in primary mammalian neurons

AU - Berezovska, O.

AU - Frosch, M.

AU - McLean, Pamela J

AU - Knowles, R.

AU - Koo, E.

AU - Kang, D.

AU - Shen, J.

AU - Lu, F. M.

AU - Lux, S. E.

AU - Tonegawa, S.

AU - Hyman, B. T.

PY - 1999

Y1 - 1999

N2 - The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin-12, Notch1, is a transmembrane receptor that plays an important role in cell fate decisions during development, including neurogenesis, but does not have a known function in fully differentiated cells. To better understand the potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 transfection on neurite outgrowth in primary cultures of hippocampal/cortical neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furthermore, we present evidence demonstrating that there is a functional interaction between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin-12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibitory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overexpressing wild type PS1, but not mutant PS1. These data suggest that PS1 facilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons. Copyright (C) 1999 Elsevier Science B.V.

AB - The normal functional neurobiology of the Alzheimer's disease (AD) related gene presenilin 1 (PS1) is unknown. One clue comes from a genetic screen of Caenorhabditis elegans, which reveals that the presenilin homologue sel-12 facilitates lin-12 function [D. Levitan, I. Greenwald, Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene, Nature 377 (1995) 351-355]. The mammalian homologue of lin-12, Notch1, is a transmembrane receptor that plays an important role in cell fate decisions during development, including neurogenesis, but does not have a known function in fully differentiated cells. To better understand the potential role of Notch1 in mammalian postmitotic neurons and to test the hypothesis that Notch and PS 1 interact, we studied the effect of Notch1 transfection on neurite outgrowth in primary cultures of hippocampal/cortical neurons. We demonstrate that Notch1 inhibits neurite extension, and thus has a function in postmitotic mature neurons in the mammalian CNS. Furthermore, we present evidence demonstrating that there is a functional interaction between PS1 and Notch1 in mammalian neurons, analogous to the sel-12/lin-12 interaction in vulval development in C. elegans [D. Levitan, T. Doyle, D. Brousseau, M. Lee, G. Thinakaran, H. Slunt, S. Sisodia, I. Greenwald, Assessment of normal and mutant human presenilin function in Caenorhabditis elegans, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14940-14944; D. Levitan, I. Greenwald, Effect of Sel-12 presenilin on Lin-12 localization and function in Caenorhabditis elegans, Development, 125 (1998) 3599-3606]. The inhibitory effect of Notch1 on neurite outgrowth is markedly attenuated in neurons from PS1 knockout mice, and enhanced in neurons from transgenic mice overexpressing wild type PS1, but not mutant PS1. These data suggest that PS1 facilitates Notch1 function in mammalian neurons, and support the hypothesis that a functional interaction exists between PS1 and Notch1 in postmitotic mammalian neurons. Copyright (C) 1999 Elsevier Science B.V.

KW - Notch1

KW - Presenilin 1

KW - Primary neurons

KW - PS1 knockout mice

KW - PS1 transgenics

UR - http://www.scopus.com/inward/record.url?scp=0033013543&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033013543&partnerID=8YFLogxK

U2 - 10.1016/S0169-328X(99)00119-9

DO - 10.1016/S0169-328X(99)00119-9

M3 - Article

C2 - 10366748

AN - SCOPUS:0033013543

VL - 69

SP - 273

EP - 280

JO - Brain Research

JF - Brain Research

SN - 0006-8993

IS - 2

ER -