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

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.

[1]  B. Hyman,et al.  Notch1 inhibits neurite outgrowth in postmitotic primary neurons , 1999, Neuroscience.

[2]  Iva Greenwald,et al.  Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene , 1995, Nature.

[3]  I. Greenwald,et al.  Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans. , 1998, Development.

[4]  C. Haass,et al.  Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. , 1997, Genes and function.

[5]  Gerald M. Rubin,et al.  Making a difference: The role of cell-cell interactions in establishing separate identities for equivalent cells , 1992, Cell.

[6]  Gurparkash Singh,et al.  Mutant Human Presenilin 1 Protects presenilin 1 Null Mouse against Embryonic Lethality and Elevates Aβ1–42/43 Expression , 1998, Neuron.

[7]  M. Rudnicki,et al.  Simplified mammalian DNA isolation procedure. , 1991, Nucleic acids research.

[8]  D. Wettstein,et al.  The Xenopus homolog of Drosophila Suppressor of Hairless mediates Notch signaling during primary neurogenesis. , 1997, Development.

[9]  I. Greenwald,et al.  Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[10]  D. Selkoe,et al.  Subcellular Distribution and Turnover of Presenilins in Transfected Cells* , 1998, The Journal of Biological Chemistry.

[11]  S E Lux,et al.  Constitutively active human Notch1 binds to the transcription factor CBF1 and stimulates transcription through a promoter containing a CBF1-responsive element. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Cepko,et al.  The Expression and Function of Notch Pathway Genes in the Developing Rat Eye , 1997, The Journal of Neuroscience.

[13]  S. Tonegawa,et al.  Skeletal and CNS Defects in Presenilin-1-Deficient Mice , 1997, Cell.

[14]  G. Weinmaster,et al.  Notch1 is essential for postimplantation development in mice. , 1994, Genes & development.

[15]  A. Chitnis.  The Role of Notch in Lateral Inhibition and Cell Fate Specification , 1995, Molecular and Cellular Neuroscience.

[16]  E. Giniger.  A Role for Abl in Notch Signaling , 1998, Neuron.

[17]  W. Harris,et al.  Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos , 1993, Cell.

[18]  J. Freedman,et al.  polychaetoid is required to restrict segregation of sensory organ precursors from proneural clusters in Drosophila , 1996, Mechanisms of Development.

[19]  Raphael Kopan,et al.  An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells. , 1994, Development.

[20]  Weiming Xia,et al.  Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice , 1997, Nature Medicine.

[21]  S. Artavanis-Tsakonas,et al.  Choosing a cell fate: a view from the Notch locus. , 1991, Trends in genetics : TIG.

[22]  M. Greenberg,et al.  Calcium Influx via the NMDA Receptor Induces Immediate Early Gene Transcription by a MAP Kinase/ERK-Dependent Mechanism , 1996, The Journal of Neuroscience.

[23]  Kenji Matsuno,et al.  Notch signaling. , 1995, Science.

[24]  G. Weinmaster,et al.  Notch2: a second mammalian Notch gene. , 1992, Development.

[25]  R. Greenspan,et al.  The Notch locus of Drosophila is required in epidermal cells for epidermal development. , 1990, Development.

[26]  C. Cepko,et al.  Vertebrate retinal ganglion cells are selected from competent progenitors by the action of Notch. , 1995, Development.

[27]  W. Harris,et al.  Regulation of neuronal diversity in the Xenopus retina by Delta signalling , 1997, Nature.

[28]  C. Doe,et al.  Sanpodo and Notch act in opposition to Numb to distinguish sibling neuron fates in the Drosophila CNS. , 1998, Development.

[29]  Kenneth S. Kosik,et al.  The E280A presenilin 1 Alzheimer mutation produces increased Aβ42 deposition and severe cerebellar pathology , 1996, Nature Medicine.

[30]  S. Mcconnell,et al.  Cleavage orientation and the asymmetric inheritance of notchl immunoreactivity in mammalian neurogenesis , 1995, Cell.

[31]  Allan I. Levey,et al.  Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo , 1996, Neuron.

[32]  B. Hyman,et al.  Developmental Regulation of Presenilin mRNA Expression Parallels Notch Expression , 1997, Journal of neuropathology and experimental neurology.

[33]  D. Bonthron,et al.  PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model , 1991, Cell.

[34]  D. Price,et al.  Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm , 1997, Nature.

[35]  B. Hyman,et al.  Notch Is Expressed in Adult Brain, Is Coexpressed with Presenilin-1, and Is Altered in Alzheimer Disease , 1998, Journal of neuropathology and experimental neurology.

[36]  S. Artavanis-Tsakonas,et al.  Involvement of Notch-1 in mammalian retinal neurogenesis: association of Notch-1 activity with both immature and terminally differentiated cells , 1995, Mechanisms of Development.

[37]  H. Weintraub,et al.  The intracellular domain of mouse Notch: a constitutively activated repressor of myogenesis directed at the basic helix-loop-helix region of MyoD. , 1994, Development.

[38]  D. Borchelt,et al.  An Alzheimer's Disease-Linked PS1 Variant Rescues the Developmental Abnormalities of PS1-Deficient Embryos , 1998, Neuron.