Lamin B1 Polymorphism Influences Morphology of the Nuclear Envelope, Cell Cycle Progression, and Risk of Neural Tube Defects in Mice

English version České info

Neural tube defects (NTDs), including spina bifida and anencephaly, are common birth defects whose complex multigenic causation has hampered efforts to delineate their molecular basis. The effect of putative modifier genes in determining NTD susceptibility may be investigated in mouse models, particularly those that display partial penetrance such as curly tail, a strain in which NTDs result from a hypomorphic allele of the grainyhead-like-3 gene. Through proteomic analysis, we found that the curly tail genetic background harbours a polymorphic variant of lamin B1, lacking one of a series of nine glutamic acid residues. Lamins are intermediate filament proteins of the nuclear lamina with multiple functions that influence nuclear structure, cell cycle properties, and transcriptional regulation. Fluorescence loss in photobleaching showed that the variant lamin B1 exhibited reduced stability in the nuclear lamina. Genetic analysis demonstrated that the variant also affects neural tube closure: the frequency of spina bifida and anencephaly was reduced three-fold when wild-type lamin B1 was bred into the curly tail strain background. Cultured fibroblasts expressing variant lamin B1 show significantly increased nuclear dysmorphology and diminished proliferative capacity, as well as premature senescence, associated with reduced expression of cyclins and Smc2, and increased expression of p16. The cellular basis of spinal NTDs in curly tail embryos involves a proliferation defect localised to the hindgut epithelium, and S-phase progression was diminished in the hindgut of embryos expressing variant lamin B1. These observations indicate a mechanistic link between altered lamin B1 function, exacerbation of the Grhl3-mediated cell proliferation defect, and enhanced susceptibility to NTDs. We conclude that lamin B1 is a modifier gene of major effect for NTDs resulting from loss of Grhl3 function, a role that is likely mediated via the key function of lamin B1 in maintaining integrity of the nuclear envelope and ensuring normal cell cycle progression.

Vyšlo v časopise: Lamin B1 Polymorphism Influences Morphology of the Nuclear Envelope, Cell Cycle Progression, and Risk of Neural Tube Defects in Mice. PLoS Genet 8(11): e32767. doi:10.1371/journal.pgen.1003059
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003059

Souhrn

Zdroje

1. NadeauJH (2003) Modifier genes and protective alleles in humans and mice. Curr Opin Genet Dev 13: 290–295.

2. CoppAJ, GreeneNDE (2010) Genetics and development of neural tube defects. J Pathol 220: 217–230.

3. BassukAG, KibarZ (2009) Genetic basis of neural tube defects. Semin Pediatr Neurol 16: 101–110.

4. GreeneNDE, StanierP, CoppAJ (2009) Genetics of human neural tube defects. Hum Mol Genet 18: R113–R129.

5. CoppAJ, GreeneNDE, MurdochJN (2003) The genetic basis of mammalian neurulation. Nat Rev Genet 4: 784–793.

6. HarrisMJ, JuriloffDM (2010) An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Res A Clin Mol Teratol 88: 653–669.

7. HarrisMJ, JuriloffDM (2007) Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects. Birth Defects Res A Clin Mol Teratol 79: 187–210.

8. Van StraatenHWM, CoppAJ (2001) Curly tail: a 50-year history of the mouse spina bifida model. Anat Embryol 203: 225–237.

9. GustavssonP, GreeneND, LadD, PauwsE, de CastroSC, et al. (2007) Increased expression of Grainyhead-like-3 rescues spina bifida in a folate-resistant mouse model. Hum Mol Genet 16: 2640–2646.

10. TingSB, WilanowskiT, AudenA, HallM, VossAK, et al. (2003) Inositol- and folate-resistant neural tube defects in mice lacking the epithelial-specific factor Grhl-3. Nature Med 9: 1513–1519.

11. YuZ, LinKK, BhandariA, SpencerJA, XuX, et al. (2006) The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4. Dev Biol 299: 122–136.

12. CoppAJ, BrookFA, RobertsHJ (1988) A cell-type-specific abnormality of cell proliferation in mutant (curly tail) mouse embryos developing spinal neural tube defects. Development 104: 285–295.

13. GustavssonP, CoppAJ, GreeneND (2008) Grainyhead genes and mammalian neural tube closure. Birth Defects Res A Clin Mol Teratol 82: 728–735.

14. BrookFA, ShumASW, Van StraatenHWM, CoppAJ (1991) Curvature of the caudal region is responsible for failure of neural tube closure in the curly tail (ct) mouse embryo. Development 113: 671–678.

15. ChenW-H, Morriss-KayGM, CoppAJ (1995) Genesis and prevention of spinal neural tube defects in the curly tail mutant mouse: involvement of retinoic acid and its nuclear receptors RAR-beta and RAR-gamma. Development 121: 681–691.

16. CoppAJ, CrollaJA, BrookFA (1988) Prevention of spinal neural tube defects in the mouse embryo by growth retardation during neurulation. Development 104: 297–303.

17. GreeneNDE, CoppAJ (1997) Inositol prevents folate-resistant neural tube defects in the mouse. Nature Med 3: 60–66.

18. BurrenKA, ScottJM, CoppAJ, GreeneND (2010) The genetic background of the curly tail strain confers susceptibility to folate-deficiency-induced exencephaly. Birth Defects Res A Clin Mol Teratol 88: 76–83.

19. NeumannPE, FrankelWN, LettsVA, CoffinJM, CoppAJ, et al. (1994) Multifactorial inheritance of neural tube defects: Localization of the major gene and recognition of modifiers in ct mutant mice. Nature Genet 6: 357–362.

20. CapellBC, CollinsFS (2006) Human laminopathies: nuclei gone genetically awry. Nat Rev Genet 7: 940–952.

21. GruenbaumY, MargalitA, GoldmanRD, ShumakerDK, WilsonKL (2005) The nuclear lamina comes of age. Nat Rev Mol Cell Biol 6: 21–31.

22. WormanHJ, FongLG, MuchirA, YoungSG (2009) Laminopathies and the long strange trip from basic cell biology to therapy. J Clin Invest 119: 1825–1836.

23. HutchisonCJ (2002) Lamins: building blocks or regulators of gene expression? Nat Rev Mol Cell Biol 3: 848–858.

24. DechatT, PfleghaarK, SenguptaK, ShimiT, ShumakerDK, et al. (2008) Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin. Genes Dev 22: 832–853.

25. GoldmanRD, GruenbaumY, MoirRD, ShumakerDK, SpannTP (2002) Nuclear lamins: building blocks of nuclear architecture. Genes Dev 16: 533–547.

26. MalhasA, LeeCF, SandersR, SaundersNJ, VauxDJ (2007) Defects in lamin B1 expression or processing affect interphase chromosome position and gene expression. J Cell Biol 176: 593–603.

27. MalhasA, SaundersNJ, VauxDJ (2010) The nuclear envelope can control gene expression and cell cycle progression via miRNA regulation. Cell Cycle 9: 531–539.

28. MekhailK, MoazedD (2010) The nuclear envelope in genome organization, expression and stability. Nat Rev Mol Cell Biol 11: 317–328.

29. KimY, SharovAA, McDoleK, ChengM, HaoH, et al. (2011) Mouse B-type lamins are required for proper organogenesis but not by embryonic stem cells. Science 334: 1706–1710.

30. WormanHJ, OstlundC, WangY (2010) Diseases of the nuclear envelope. Cold Spring Harb Perspect Biol 2: a000760.

31. PadiathQS, SaigohK, SchiffmannR, AsaharaH, YamadaT, et al. (2006) Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat Genet 38: 1114–1123.

32. SchusterJ, SundblomJ, ThuressonAC, Hassin-BaerS, KlopstockT, et al. (2011) Genomic duplications mediate overexpression of lamin B1 in adult-onset autosomal dominant leukodystrophy (ADLD) with autonomic symptoms. Neurogenetics 12: 65–72.

33. VergnesL, PeterfyM, BergoMO, YoungSG, ReueK (2004) Lamin B1 is required for mouse development and nuclear integrity. Proc Natl Acad Sci U S A 101: 10428–10433.

34. CoffinierC, JungHJ, NobumoriC, ChangS, TuY, et al. (2011) Deficiencies in lamin B1 and lamin B2 cause neurodevelopmental defects and distinct nuclear shape abnormalities in neurons. Mol Biol Cell 22: 4683–4693.

35. CoffinierC, ChangSY, NobumoriC, TuY, FarberEA, et al. (2010) Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency. Proc Natl Acad Sci U S A 107: 5076–5081.

36. JonesDT (1999) Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 292: 195–202.

37. SubramanianG, HjelmRP, DemingTJ, SmithGS, LiY, SafinyaCR (2000) Structure of complexes of cationic lipids and poly(glutamic acid) polypeptides: a pinched lamellar phase. J Am Chem Soc 122: 26–34.

38. GrunebergH (1954) Genetical studies on the skeleton of the mouse. VIII. Curly tail. J Genet 52: 52–67.

39. BeecheyCV, SearleAG (1986) Mutations at the Sp locus. Mouse News Letter 75: 28.

40. CoppAJ (1985) Relationship between timing of posterior neuropore closure and development of spinal neural tube defects in mutant (curly tail) and normal mouse embryos in culture. J Embryol Exp Morphol 88: 39–54.

41. De CastroSC, LeungKY, SaveryD, BurrenK, RozenR, et al. (2010) Neural tube defects induced by folate deficiency in mutant curly tail (Grhl3) embryos are associated with alteration in folate one-carbon metabolism but are unlikely to result from diminished methylation. Birth Defects Res A Clin Mol Teratol 88: 612–618.

42. ScaffidiP, MisteliT (2005) Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nature Med 11: 440–445.

43. BudirahardjaY, GonczyP (2009) Coupling the cell cycle to development. Development 136: 2861–2872.

44. HocheggerH, TakedaS, HuntT (2008) Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol 9: 910–916.

45. LiJ, PoiMJ, TsaiMD (2011) Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to cancer. Biochemistry 50: 5566–5582.

46. LegagneuxV, CubizollesF, WatrinE (2004) Multiple roles of Condensins: a complex story. Biol Cell 96: 201–213.

47. FazzioTG, PanningB (2010) Condensin complexes regulate mitotic progression and interphase chromatin structure in embryonic stem cells. J Cell Biol 188: 491–503.

48. ShimiT, PfleghaarK, KojimaS, PackCG, SoloveiI, et al. (2008) The A- and B-type nuclear lamin networks: microdomains involved in chromatin organization and transcription. Genes Dev 22: 3409–3421.

49. TsaiMY, WangS, HeidingerJM, ShumakerDK, AdamSA, et al. (2006) A mitotic lamin B matrix induced by RanGTP required for spindle assembly. Science 311: 1887–1893.

50. MoirRD, SpannTP, HerrmannH, GoldmanRD (2000) Disruption of nuclear lamin organization blocks the elongation phase of DNA replication. J Cell Biol 149: 1179–1192.

51. MalhasAN, LeeCF, VauxDJ (2009) Lamin B1 controls oxidative stress responses via Oct-1. J Cell Biol 184: 45–55.

52. GongD, PomereningJR, MyersJW, GustavssonC, JonesJT, et al. (2007) Cyclin A2 regulates nuclear-envelope breakdown and the nuclear accumulation of cyclin B1. Curr Biol 17: 85–91.

53. ShimiT, Butin-IsraeliV, AdamSA, HamanakaRB, GoldmanAE, et al. (2011) The role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev 25: 2579–2593.

54. SellerMJ, PerkinsKJ (1986) Effect of mitomycin C on the neural tube defects of the curly-tail mouse. Teratology 33: 305–309.

55. GreeneND, BamideleA, ChoyM, de CastroSC, WaitR, et al. (2007) Proteome changes associated with hippocampal MRI abnormalities in the lithium pilocarpine-induced model of convulsive status epilepticus. Proteomics 7: 1336–1344.

56. GreeneNDE, LeungKY, WaitR, BegumS, DunnMJ, et al. (2002) Differential protein expression at the stage of neural tube closure in the mouse embryo. J Biol Chem 277: 41645–41651.

57. MaskeCP, HollinsheadMS, HigbeeNC, BergoMO, YoungSG, et al. (2003) A carboxyl-terminal interaction of lamin B1 is dependent on the CAAX endoprotease Rce1 and carboxymethylation. J Cell Biol 162: 1223–1232.