Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1998 Aug 17;17(16):4647–4656. doi: 10.1093/emboj/17.16.4647

APLP2, a member of the Alzheimer precursor protein family, is required for correct genomic segregation in dividing mouse cells.

M Rassoulzadegan 1, Y Yang 1, F Cuzin 1
PMCID: PMC1170794  PMID: 9707424

Abstract

The mouse amyloid precursor-like protein 2 (APLP2) belongs to the Alzheimer peptide precursor family. A possible role in pre-implantation development had been suggested previously, and was investigated further by creating a large deletion in the genomic locus. While heterozygous mice developed normally, homozygous embryos were arrested before reaching the blastocyst stage. One-cell embryos which contained protein of maternal origin underwent a limited number of cleavages. The progressive disappearance of the protein at stages 4 and beyond correlated with the appearance of extensive cytopathological effects. Nuclear DNA contents of the arrested embryos departed widely from the normal 2-4C value, thus suggesting a role for the protein in replication and/or segregation of the embryonic genome. Embryonic mortality was not due to the untimely initiation of programmed cell death, and it occurred before the stage at which apoptotic cells normally appear. The same abnormal distribution of DNA contents was seen in primary cultures of Aplp2 +/- embryonic fibroblasts following transfection of an expression vector for Aplp2 antisense RNA with green fluorescent protein (GFP) expressed from a co-transfected construct. Daughter cells derived from a GFP-positive cell showed abnormal DNA contents both >4C and <2C, thus indicating a role for the protein in the mitotic segregation of the genome and establishment of the proper nuclear structure.

Full Text

The Full Text of this article is available as a PDF (496.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blangy A., Léopold P., Vidal F., Rassoulzadegan M., Cuzin F. Recognition of the CDEI motif GTCACATG by mouse nuclear proteins and interference with the early development of the mouse embryo. Nucleic Acids Res. 1991 Dec;19(25):7243–7250. doi: 10.1093/nar/19.25.7243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Blangy A., Vidal F., Cuzin F., Yang Y. H., Boulukos K., Rassoulzadegan M. CDEBP, a site-specific DNA-binding protein of the 'APP-like' family, is required during the early development of the mouse. J Cell Sci. 1995 Feb;108(Pt 2):675–683. doi: 10.1242/jcs.108.2.675. [DOI] [PubMed] [Google Scholar]
  3. Chauhan S. S., Gottesman M. M. Construction of a new universal vector for insertional mutagenesis by homologous recombination. Gene. 1992 Oct 21;120(2):281–285. doi: 10.1016/0378-1119(92)90106-y. [DOI] [PubMed] [Google Scholar]
  4. Coucouvanis E., Martin G. R. Signals for death and survival: a two-step mechanism for cavitation in the vertebrate embryo. Cell. 1995 Oct 20;83(2):279–287. doi: 10.1016/0092-8674(95)90169-8. [DOI] [PubMed] [Google Scholar]
  5. Daigle I., Li C. apl-1, a Caenorhabditis elegans gene encoding a protein related to the human beta-amyloid protein precursor. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):12045–12049. doi: 10.1073/pnas.90.24.12045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. El-Shershaby A. M., Hinchliffe J. R. Cell redundancy in the zona-intact preimplantation mouse blastocyst: a light and electron microscope study of dead cells and their fate. J Embryol Exp Morphol. 1974 Jun;31(3):643–654. [PubMed] [Google Scholar]
  7. Ellis L., Clauser E., Morgan D. O., Edery M., Roth R. A., Rutter W. J. Replacement of insulin receptor tyrosine residues 1162 and 1163 compromises insulin-stimulated kinase activity and uptake of 2-deoxyglucose. Cell. 1986 Jun 6;45(5):721–732. doi: 10.1016/0092-8674(86)90786-5. [DOI] [PubMed] [Google Scholar]
  8. Hanes J., von der Kammer H., Kristjansson G. I., Scheit K. H. The complete cDNA coding sequence for the mouse CDEI binding protein. Biochim Biophys Acta. 1993 Oct 19;1216(1):154–156. doi: 10.1016/0167-4781(93)90055-i. [DOI] [PubMed] [Google Scholar]
  9. Ioffe E., Liu Y., Bhaumik M., Poirier F., Factor S. M., Stanley P. WW6: an embryonic stem cell line with an inert genetic marker that can be traced in chimeras. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7357–7361. doi: 10.1073/pnas.92.16.7357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Li J., Xu M., Zhou H., Ma J., Potter H. Alzheimer presenilins in the nuclear membrane, interphase kinetochores, and centrosomes suggest a role in chromosome segregation. Cell. 1997 Sep 5;90(5):917–927. doi: 10.1016/s0092-8674(00)80356-6. [DOI] [PubMed] [Google Scholar]
  11. Mortensen R. M., Conner D. A., Chao S., Geisterfer-Lowrance A. A., Seidman J. G. Production of homozygous mutant ES cells with a single targeting construct. Mol Cell Biol. 1992 May;12(5):2391–2395. doi: 10.1128/mcb.12.5.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Müller U., Cristina N., Li Z. W., Wolfer D. P., Lipp H. P., Rülicke T., Brandner S., Aguzzi A., Weissmann C. Behavioral and anatomical deficits in mice homozygous for a modified beta-amyloid precursor protein gene. Cell. 1994 Dec 2;79(5):755–765. doi: 10.1016/0092-8674(94)90066-3. [DOI] [PubMed] [Google Scholar]
  13. Pierrefite V., Binetruy B., Rassoulzadegan M., Cuzin F. Conditional requirement for sequences distinct from the replication origin during episomal establishment of the BPV1 genome. Biochem Biophys Res Commun. 1996 Dec 13;229(2):445–448. doi: 10.1006/bbrc.1996.1823. [DOI] [PubMed] [Google Scholar]
  14. Pierrefite V., Cuzin F. Replication efficiency of bovine papillomavirus type 1 DNA depends on cis-acting sequences distinct from the replication origin. J Virol. 1995 Dec;69(12):7682–7687. doi: 10.1128/jvi.69.12.7682-7687.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Porter A. Controlling your losses: conditional gene silencing in mammals. Trends Genet. 1998 Feb;14(2):73–79. doi: 10.1016/s0168-9525(97)01326-7. [DOI] [PubMed] [Google Scholar]
  16. Rosen D. R., Martin-Morris L., Luo L. Q., White K. A Drosophila gene encoding a protein resembling the human beta-amyloid protein precursor. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2478–2482. doi: 10.1073/pnas.86.7.2478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sandbrink R., Masters C. L., Beyreuther K. Complete nucleotide and deduced amino acid sequence of rat amyloid protein precursor-like protein 2 (APLP2/APPH): two amino acids length difference to human and murine homologues. Biochim Biophys Acta. 1994 Sep 13;1219(1):167–170. doi: 10.1016/0167-4781(94)90263-1. [DOI] [PubMed] [Google Scholar]
  18. Sandbrink R., Masters C. L., Beyreuther K. Similar alternative splicing of a non-homologous domain in beta A4-amyloid protein precursor-like proteins. J Biol Chem. 1994 May 13;269(19):14227–14234. [PubMed] [Google Scholar]
  19. Seif R., Cuzin F. Temperature-sensitive growth regulation in one type of transformed rat cells induced by the tsa mutant of polyoma virus. J Virol. 1977 Dec;24(3):721–728. doi: 10.1128/jvi.24.3.721-728.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Selkoe D. J. Amyloid beta protein precursor and the pathogenesis of Alzheimer's disease. Cell. 1989 Aug 25;58(4):611–612. doi: 10.1016/0092-8674(89)90093-7. [DOI] [PubMed] [Google Scholar]
  21. Sprecher C. A., Grant F. J., Grimm G., O'Hara P. J., Norris F., Norris K., Foster D. C. Molecular cloning of the cDNA for a human amyloid precursor protein homolog: evidence for a multigene family. Biochemistry. 1993 May 4;32(17):4481–4486. doi: 10.1021/bi00068a002. [DOI] [PubMed] [Google Scholar]
  22. Thinakaran G., Kitt C. A., Roskams A. J., Slunt H. H., Masliah E., von Koch C., Ginsberg S. D., Ronnett G. V., Reed R. R., Price D. L. Distribution of an APP homolog, APLP2, in the mouse olfactory system: a potential role for APLP2 in axogenesis. J Neurosci. 1995 Oct;15(10):6314–6326. doi: 10.1523/JNEUROSCI.15-10-06314.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Thinakaran G., Sisodia S. S. Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site. J Biol Chem. 1994 Sep 2;269(35):22099–22104. [PubMed] [Google Scholar]
  24. Vidal F., Blangy A., Rassoulzadegan M., Cuzin F. A murine sequence-specific DNA binding protein shows extensive local similarities to the amyloid precursor protein. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1336–1341. doi: 10.1016/0006-291x(92)90220-f. [DOI] [PubMed] [Google Scholar]
  25. Wasco W., Bupp K., Magendantz M., Gusella J. F., Tanzi R. E., Solomon F. Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10758–10762. doi: 10.1073/pnas.89.22.10758. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wasco W., Gurubhagavatula S., Paradis M. D., Romano D. M., Sisodia S. S., Hyman B. T., Neve R. L., Tanzi R. E. Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor. Nat Genet. 1993 Sep;5(1):95–100. doi: 10.1038/ng0993-95. [DOI] [PubMed] [Google Scholar]
  27. Yang Y., Martin L., Cuzin F., Mattei M. G., Rassoulzadegan M. Genomic structure and chromosomal localization of the mouse CDEI-binding protein CDEBP (APLP2) gene and promoter sequences. Genomics. 1996 Jul 1;35(1):24–29. doi: 10.1006/geno.1996.0318. [DOI] [PubMed] [Google Scholar]
  28. Zheng H., Jiang M., Trumbauer M. E., Sirinathsinghji D. J., Hopkins R., Smith D. W., Heavens R. P., Dawson G. R., Boyce S., Conner M. W. beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell. 1995 May 19;81(4):525–531. doi: 10.1016/0092-8674(95)90073-x. [DOI] [PubMed] [Google Scholar]
  29. von Koch C. S., Lahiri D. K., Mammen A. L., Copeland N. G., Gilbert D. J., Jenkins N. A., Sisodia S. The mouse APLP2 gene. Chromosomal localization and promoter characterization. J Biol Chem. 1995 Oct 27;270(43):25475–25480. doi: 10.1074/jbc.270.43.25475. [DOI] [PubMed] [Google Scholar]
  30. von der Kammer H., Hanes J., Klaudiny J., Scheit K. H. A human amyloid precursor-like protein is highly homologous to a mouse sequence-specific DNA-binding protein. DNA Cell Biol. 1994 Nov;13(11):1137–1143. doi: 10.1089/dna.1994.13.1137. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES