A Retrotransposon Insertion in the 5′ Regulatory Domain of Ptf1a Results in Ectopic Gene Expression and Multiple Congenital Defects in Danforth's Short Tail Mouse

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Danforth's short tail mutant (Sd) mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2. Resequencing of this region identified an 8.5-kb early retrotransposon (ETn) insertion within the highly conserved regulatory sequences upstream of Pancreas Specific Transcription Factor, 1a (Ptf1a). This mutation resulted in up to tenfold increased expression of Ptf1a as compared to wild-type embryos at E9.5 but no detectable changes in the expression levels of other neighboring genes. At E9.5, Sd mutants exhibit ectopic Ptf1a expression in embryonic progenitors of every organ that will manifest a developmental defect: the notochord, the hindgut, and the mesonephric ducts. Moreover, at E 8.5, Sd mutant mice exhibit ectopic Ptf1a expression in the lateral plate mesoderm, tail bud mesenchyme, and in the notochord, preceding the onset of visible defects such as notochord degeneration. The Sd heterozygote phenotype was not ameliorated by Ptf1a haploinsufficiency, further suggesting that the developmental defects result from ectopic expression of Ptf1a. These data identify disruption of the spatio-temporal pattern of Ptf1a expression as the unifying mechanism underlying the multiple congenital defects in Danforth's short tail mouse. This striking example of an enhancer mutation resulting in profound developmental defects suggests that disruption of conserved regulatory elements may also contribute to human malformation syndromes.

Vyšlo v časopise: A Retrotransposon Insertion in the 5′ Regulatory Domain of Ptf1a Results in Ectopic Gene Expression and Multiple Congenital Defects in Danforth's Short Tail Mouse. PLoS Genet 9(2): e32767. doi:10.1371/journal.pgen.1003206
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003206

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1. ParkerSE, MaiCT, CanfieldMA, RickardR, WangY, et al. (2010) Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004–2006. Birth Defects Res A Clin Mol Teratol 88: 1008–1016.

2. Population-based birth defects surveillance data from selected states, 2000–2004. Birth Defects Res A Clin Mol Teratol 79: 874–942.

3. BoulasMM (2009) Recognition of caudal regression syndrome. Adv Neonatal Care 9: 61–69 quiz 70–61.

4. BohringA, LewinSO, ReynoldsJF, VoigtlanderT, RittingerO, et al. (1999) Polytopic anomalies with agenesis of the lower vertebral column. Am J Med Genet 87: 99–114.

5. RossAJ, Ruiz-PerezV, WangY, HaganDM, SchererS, et al. (1998) A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat Genet 20: 358–361.

6. WoolfAS, PriceKL, ScamblerPJ, WinyardPJ (2004) Evolving concepts in human renal dysplasia. J Am Soc Nephrol 15: 998–1007.

7. SchedlA (2007) Renal abnormalities and their developmental origin. Nat Rev Genet 8: 791–802.

8. WeberS, MoriniereV, KnuppelT, CharbitM, DusekJ, et al. (2006) Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol 17: 2864–2870.

9. UlinskiT, LescureS, BeaufilsS, GuigonisV, DecramerS, et al. (2006) Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 17: 497–503.

10. ThomasR, Sanna-CherchiS, WaradyBA, FurthSL, KaskelFJ, et al. (2011) HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol 26: 897–903.

11. DanforthCH (1930) Developmental Anomalies in a Special Strain of Mice. Amer Jour Anat 45: 275–287.

12. DunnLC, Gluecksohn-SchoenheimerS, BrysonV (1940) A New Mutation in the Mouse: Affecting Spinal Column and Urogenital System J Heredity. 31: 343–348.

13. Gluecksohn-SchoenheimerS (1943) The Morphological Manifestations of a Dominant Mutation in Mice Affecting Tail and Urogenital System. Genetics 28: 341–348.

14. Gluecksohn-SchoenheimerS (1945) The Embryonic Development of Mutants of the Sd-Strain in Mice. Genetics 30: 29–38.

15. GrunebergH (1958) Genetical studies on the skeleton of the mouse. XXII. The development of Danforth's short-tail. J Embryol Exp Morphol 6: 124–148.

16. AsakuraA, TapscottSJ (1998) Apoptosis of epaxial myotome in Danforth's short-tail (Sd) mice in somites that form following notochord degeneration. Dev Biol 203: 276–289.

17. MaatmanR, ZachgoJ, GosslerA (1997) The Danforth's short tail mutation acts cell autonomously in notochord cells and ventral hindgut endoderm. Development 124: 4019–4028.

18. TripathiP, GuoQ, WangY, CoussensM, LiapisH, et al. (2010) Midline signaling regulates kidney positioning but not nephrogenesis through Shh. Dev Biol 340: 518–527.

19. AlfredJB, RanceK, TaylorBA, PhillipsSJ, AbbottCM, et al. (1997) Mapping in the region of Danforth's short tail and the localization of tail length modifiers. Genome Res 7: 108–117.

20. MaksakovaIA, RomanishMT, GagnierL, DunnCA, van de LagemaatLN, et al. (2006) Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line. PLoS Genet 2: e2 doi:10.1371/journal.pgen.0020002

21. NellakerC, KeaneTM, YalcinB, WongK, AgamA, et al. (2012) The genomic landscape shaped by selection on transposable elements across 18 mouse strains. Genome Biol 13: R45.

22. Fernandez-GonzalezA, La SpadaAR, TreadawayJ, HigdonJC, HarrisBS, et al. (2002) Purkinje cell degeneration (pcd) phenotypes caused by mutations in the axotomy-induced gene, Nna1. Science 295: 1904–1906.

23. MaJ, NortonJC, AllenAC, BurnsJB, HaselKW, et al. (1995) Retinal degeneration slow (rds) in mouse results from simple insertion of a t haplotype-specific element into protein-coding exon II. Genomics 28: 212–219.

24. GittesGK (2009) Developmental biology of the pancreas: a comprehensive review. Dev Biol 326: 4–35.

25. MasuiT, SwiftGH, HaleMA, MeredithDM, JohnsonJE, et al. (2008) Transcriptional autoregulation controls pancreatic Ptf1a expression during development and adulthood. Mol Cell Biol 28: 5458–5468.

26. MeredithDM, MasuiT, SwiftGH, MacDonaldRJ, JohnsonJE (2009) Multiple transcriptional mechanisms control Ptf1a levels during neural development including autoregulation by the PTF1-J complex. J Neurosci 29: 11139–11148.

27. ObataJ, YanoM, MimuraH, GotoT, NakayamaR, et al. (2001) p48 subunit of mouse PTF1 binds to RBP-Jkappa/CBF-1, the intracellular mediator of Notch signalling, and is expressed in the neural tube of early stage embryos. Genes to cells : devoted to molecular & cellular mechanisms 6: 345–360.

28. KawaguchiY, CooperB, GannonM, RayM, MacDonaldRJ, et al. (2002) The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nature genetics 32: 128–134.

29. ThompsonN, GesinaE, ScheinertP, BucherP, Grapin-BottonA (2012) RNA profiling and chromatin immunoprecipitation-sequencing reveal that PTF1a stabilizes pancreas progenitor identity via the control of MNX1/HLXB9 and a network of other transcription factors. Molecular and cellular biology 32: 1189–1199.

30. HenkeRM, SavageTK, MeredithDM, GlasgowSM, HoriK, et al. (2009) Neurog2 is a direct downstream target of the Ptf1a-Rbpj transcription complex in dorsal spinal cord. Development 136: 2945–2954.

31. HoriK, Cholewa-WaclawJ, NakadaY, GlasgowSM, MasuiT, et al. (2008) A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling. Genes Dev 22: 166–178.

32. GlasgowSM, HenkeRM, MacdonaldRJ, WrightCV, JohnsonJE (2005) Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development 132: 5461–5469.

33. ObataJ, YanoM, MimuraH, GotoT, NakayamaR, et al. (2001) p48 subunit of mouse PTF1 binds to RBP-Jkappa/CBF-1, the intracellular mediator of Notch signalling, and is expressed in the neural tube of early stage embryos. Genes Cells 6: 345–360.

34. RouxE, StrubinM, HagenbuchleO, WellauerPK (1989) The cell-specific transcription factor PTF1 contains two different subunits that interact with the DNA. Genes Dev 3: 1613–1624.

35. KawaguchiY, CooperB, GannonM, RayM, MacDonaldRJ, et al. (2002) The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat Genet 32: 128–134.

36. MasuiT, LongQ, BeresTM, MagnusonMA, MacDonaldRJ (2007) Early pancreatic development requires the vertebrate Suppressor of Hairless (RBPJ) in the PTF1 bHLH complex. Genes Dev 21: 2629–2643.

37. BeresTM, MasuiT, SwiftGH, ShiL, HenkeRM, et al. (2006) PTF1 is an organ-specific and Notch-independent basic helix-loop-helix complex containing the mammalian Suppressor of Hairless (RBP-J) or its paralogue, RBP-L. Mol Cell Biol 26: 117–130.

38. FujitaniY, FujitaniS, LuoH, QiuF, BurlisonJ, et al. (2006) Ptf1a determines horizontal and amacrine cell fates during mouse retinal development. Development 133: 4439–4450.

39. SellickGS, BarkerKT, Stolte-DijkstraI, FleischmannC, ColemanRJ, et al. (2004) Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 36: 1301–1305.

40. MizuguchiR, KriksS, CordesR, GosslerA, MaQ, et al. (2006) Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons. Nat Neurosci 9: 770–778.

41. HoshinoM, NakamuraS, MoriK, KawauchiT, TeraoM, et al. (2005) Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47: 201–213.

42. PascualM, AbasoloI, Mingorance-Le MeurA, MartinezA, Del RioJA, et al. (2007) Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression. Proc Natl Acad Sci U S A 104: 5193–5198.

43. FukudaA, KawaguchiY, FuruyamaK, KodamaS, HoriguchiM, et al. (2006) Ectopic pancreas formation in Hes1 -knockout mice reveals plasticity of endodermal progenitors of the gut, bile duct, and pancreas. J Clin Invest 116: 1484–1493.

44. ZachgoJ, KornR, GosslerA (1998) Genetic interactions suggest that Danforth's short tail (Sd) is a gain-of-function mutation. Dev Genet 23: 86–96.

45. KleinjanDA, van HeyningenV (2005) Long-range control of gene expression: emerging mechanisms and disruption in disease. Am J Hum Genet 76: 8–32.

46. WoolfeA, GoodsonM, GoodeDK, SnellP, McEwenGK, et al. (2005) Highly conserved non-coding sequences are associated with vertebrate development. PLoS Biol 3: e7 doi:10.1371/journal.pbio.0030007

47. WoolfeA, ElgarG (2008) Organization of conserved elements near key developmental regulators in vertebrate genomes. Adv Genet 61: 307–338.

48. Sanna-CherchiS, KirylukK, BurgessK, BodriaM, SampsonM, et al. (2012) Copy Number Disorders are a Common Cause of Congenital Kidney Malformations. Am J Hum Genet (in press).

49. KeaneTM, GoodstadtL, DanecekP, WhiteMA, WongK, et al. (2011) Mouse genomic variation and its effect on phenotypes and gene regulation. Nature 477: 289–294.

50. KohanyO, GentlesAJ, HankusL, JurkaJ (2006) Annotation, submission and screening of repetitive elements in Repbase: RepbaseSubmitter and Censor. BMC Bioinformatics 7: 474.

51. WilkinsonDG, NietoMA (1993) Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol 225: 361–373.