Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome


Autoři: Terren K. Niethamer aff001;  Teng Teng aff001;  Melanie Franco aff001;  Yu Xin Du aff001;  Christopher J. Percival aff005;  Jeffrey O. Bush aff001
Působiště autorů: Program in Craniofacial Biology, University of California San Francisco, San Francisco, California, United States of America aff001;  Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, California, United States of America aff002;  Institute for Human Genetics, University of California San Francisco, San Francisco, California, United States of America aff003;  Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, California, United States of America aff004;  Department of Anthropology, Stony Brook University, Stony Brook, New York, United States of America aff005
Vyšlo v časopise: Aberrant cell segregation in the craniofacial primordium and the emergence of facial dysmorphology in craniofrontonasal syndrome. PLoS Genet 16(2): e32767. doi:10.1371/journal.pgen.1008300
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008300

Souhrn

Craniofrontonasal syndrome (CFNS) is a rare X-linked disorder characterized by craniofacial, skeletal, and neurological anomalies and is caused by mutations in EFNB1. Heterozygous females are more severely affected by CFNS than hemizygous males, a phenomenon called cellular interference that results from EPHRIN-B1 mosaicism. In Efnb1 heterozygous mice, mosaicism for EPHRIN-B1 results in cell sorting and more severe phenotypes than Efnb1 hemizygous males, but how craniofacial dysmorphology arises from cell segregation is unknown and CFNS etiology therefore remains poorly understood. Here, we couple geometric morphometric techniques with temporal and spatial interrogation of embryonic cell segregation in mouse mutant models to elucidate mechanisms underlying CFNS pathogenesis. By generating EPHRIN-B1 mosaicism at different developmental timepoints and in specific cell populations, we find that EPHRIN-B1 regulates cell segregation independently in early neural development and later in craniofacial development, correlating with the emergence of quantitative differences in face shape. Whereas specific craniofacial shape changes are qualitatively similar in Efnb1 heterozygous and hemizygous mutant embryos, heterozygous embryos are quantitatively more severely affected, indicating that Efnb1 mosaicism exacerbates loss of function phenotypes rather than having a neomorphic effect. Notably, neural tissue-specific disruption of Efnb1 does not appear to contribute to CFNS craniofacial dysmorphology, but its disruption within neural crest cell-derived mesenchyme results in phenotypes very similar to widespread loss. EPHRIN-B1 can bind and signal with EPHB1, EPHB2, and EPHB3 receptor tyrosine kinases, but the signaling partner(s) relevant to CFNS are unknown. Geometric morphometric analysis of an allelic series of Ephb1; Ephb2; Ephb3 mutant embryos indicates that EPHB2 and EPHB3 are key receptors mediating Efnb1 hemizygous-like phenotypes, but the complete loss of EPHB1-3 does not fully recapitulate the severity of CFNS-like Efnb1 heterozygosity. Finally, by generating Efnb1+/Δ; Ephb1; Ephb2; Ephb3 quadruple knockout mice, we determine how modulating cumulative receptor activity influences cell segregation in craniofacial development and find that while EPHB2 and EPHB3 play an important role in craniofacial cell segregation, EPHB1 is more important for cell segregation in the brain; surprisingly, complete loss of EPHB1-EPHB3 does not completely abrogate cell segregation. Together, these data advance our understanding of the etiology and signaling interactions underlying CFNS dysmorphology.

Klíčová slova:

Cerebrum – Embryos – Face – Morphometry – Mutant genotypes – Palate – Phenotypes – Variant genotypes


Zdroje

1. Shaw W. Global strategies to reduce the health care burden of craniofacial anomalies: report of WHO meetings on international collaborative research on craniofacial anomalies. Cleft Palate-Craniofacial J Off Publ Am Cleft Palate-Craniofacial Assoc. 2004;41: 238–243. doi: 10.1597/03-214.1 15151440

2. Twigg SRF, Wilkie AOM. New insights into craniofacial malformations. Hum Mol Genet. 2015;24: R50–59. doi: 10.1093/hmg/ddv228 26085576

3. Cohen MM Jr. Craniofrontonasal dysplasia. Birth Defects Orig Artic Ser. 1979;15: 85–9.

4. Twigg SRF, Kan R, Babbs C, Bochukova EG, Robertson SP, Wall SA, et al. Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A. 2004;101: 8652–8657. doi: 10.1073/pnas.0402819101 15166289

5. Wieland I, Jakubiczka S, Muschke P, Cohen M, Thiele H, Gerlach KL, et al. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome. Am J Hum Genet. 2004;74: 1209–1215. doi: 10.1086/421532 15124102

6. Wieacker P, Wieland I. Clinical and genetic aspects of craniofrontonasal syndrome: towards resolving a genetic paradox. Mol Genet Metab. 2005;86: 110–116. doi: 10.1016/j.ymgme.2005.07.017 16143553

7. van den Elzen MEP, Twigg SRF, Goos J a. C, Hoogeboom AJM, van den Ouweland AMW, Wilkie AOM, et al. Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1. Eur J Hum Genet EJHG. 2014;22: 995–1001. doi: 10.1038/ejhg.2013.273 24281372

8. Davy A, Aubin J, Soriano P. Ephrin-B1 forward and reverse signaling are required during mouse development. Genes Dev. 2004;18: 572–83. doi: 10.1101/gad.1171704 15037550

9. Davy A, Bush JO, Soriano P. Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol. 2006;4: e315. doi: 10.1371/journal.pbio.0040315 16968134

10. Nguyen TM, Arthur A, Paton S, Hemming S, Panagopoulos R, Codrington J, et al. Loss of ephrinB1 in osteogenic progenitor cells impedes endochondral ossification and compromises bone strength integrity during skeletal development. Bone. 2016;93: 12–21. doi: 10.1016/j.bone.2016.09.009 27622886

11. Marcucio RS, Young NM, Hu D, Hallgrimsson B. Mechanisms that underlie co-variation of the brain and face. Genes N Y N 2000. 2011;49: 177–189. doi: 10.1002/dvg.20710 21381182

12. Marcucio R, Hallgrimsson B, Young NM. Facial Morphogenesis: Physical and Molecular Interactions Between the Brain and the Face. Curr Top Dev Biol. 2015;115: 299–320. doi: 10.1016/bs.ctdb.2015.09.001 26589930

13. Boughner JC, Wat S, Diewert VM, Young NM, Browder LW, Hallgrimsson B. Short-faced mice and developmental interactions between the brain and the face. J Anat. 2008;213: 646–62. doi: 10.1111/j.1469-7580.2008.00999.x 19094181

14. Weinberg SM, Andreasen NC, Nopoulos P. Three-dimensional morphometric analysis of brain shape in nonsyndromic orofacial clefting. J Anat. 2009;214: 926–936. doi: 10.1111/j.1469-7580.2009.01084.x 19538636

15. Parsons TE, Schmidt EJ, Boughner JC, Jamniczky HA, Marcucio RS, Hallgrímsson B. Epigenetic integration of the developing brain and face. Dev Dyn Off Publ Am Assoc Anat. 2011;240: 2233–2244. doi: 10.1002/dvdy.22729 21901785

16. Young NM, Wat S, Diewert VM, Browder LW, Hallgrímsson B. Comparative morphometrics of embryonic facial morphogenesis: implications for cleft-lip etiology. Anat Rec Hoboken NJ 2007. 2007;290: 123–139. doi: 10.1002/ar.20415 17441205

17. Hu D, Young NM, Xu Q, Jamniczky H, Green RM, Mio W, et al. Signals from the brain induce variation in avian facial shape. Dev Dyn. 2015;244: 1133–1143. doi: 10.1002/dvdy.24284 25903813

18. Marcucio RS, Cordero DR, Hu D, Helms JA. Molecular interactions coordinating the development of the forebrain and face. Dev Biol. 2005;284: 48–61. doi: 10.1016/j.ydbio.2005.04.030 15979605

19. Schneider RA, Hu D, Rubenstein JLR, Maden M, Helms JA. Local retinoid signaling coordinates forebrain and facial morphogenesis by maintaining FGF8 and SHH. Development. 2001;128: 2755–2767. 11526081

20. Young NM, Chong HJ, Hu D, Hallgrímsson B, Marcucio RS. Quantitative analyses link modulation of sonic hedgehog signaling to continuous variation in facial growth and shape. Dev Camb Engl. 2010;137: 3405–3409. doi: 10.1242/dev.052340 20826528

21. Hukki J, Saarinen P, Kangasniemi M. Single suture craniosynostosis: diagnosis and imaging. Craniofacial Sutures. Karger Publishers; 2008. pp. 79–90.

22. Heuzé Y, Martínez-Abadías N, Stella JM, Senders CW, Boyadjiev SA, Lo L-J, et al. Unilateral and bilateral expression of a quantitative trait: asymmetry and symmetry in coronal craniosynostosis. J Exp Zoolog B Mol Dev Evol. 2012;318: 109–122.

23. Bastir M, Rosas A. Correlated variation between the lateral basicranium and the face: a geometric morphometric study in different human groups. Arch Oral Biol. 2006;51: 814–824. doi: 10.1016/j.archoralbio.2006.03.009 16681992

24. Parsons TE, Downey CM, Jirik FR, Hallgrimsson B, Jamniczky HA. Mind the Gap: Genetic Manipulation of Basicranial Growth within Synchondroses Modulates Calvarial and Facial Shape in Mice through Epigenetic Interactions. PLoS ONE. 2015;10: 1–22.

25. Martínez-Abadías N, Percival C, Aldridge K, Hill C, Ryan T, Sirivunnabood S, et al. Beyond the closed suture in Apert mouse models: evidence of primary effects of FGFR2 signaling on facial shape at P0. Dev Dyn. 2010;239: 3058–3071.

26. Hill CA, Martínez-Abadías N, Motch SM, Austin JR, Wang Y, Jabs EW, et al. Postnatal brain and skull growth in an Apert syndrome mouse model. Am J Med Genet A. 2013;161: 745–757.

27. Li X, Young NM, Tropp S, Hu D, Xu Y, Hallgrímsson B, et al. Quantification of shape and cell polarity reveals a novel mechanism underlying malformations resulting from related FGF mutations during facial morphogenesis. Hum Mol Genet. 2013;22: 5160–5172. doi: 10.1093/hmg/ddt369 23906837

28. Batlle E, Wilkinson DG. Molecular Mechanisms of Cell Segregation and Boundary Formation in Development and Tumorigenesis. Cold Spring Harb Perspect Biol. 2012;4: a008227–a008227. doi: 10.1101/cshperspect.a008227 22214769

29. Fagotto F, Winklbauer R, Rohani N. Ephrin-Eph signaling in embryonic tissue separation. Cell Adhes Migr. 2014;8: 308–326. doi: 10.4161/19336918.2014.970028 25482630

30. Kania A, Klein R. Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat Rev Mol Cell Biol. 2016;advance online publication. doi: 10.1038/nrm.2015.16 26790531

31. Klein R, Kania A. Ephrin signalling in the developing nervous system. Curr Opin Neurobiol. 2014;27: 16–24. doi: 10.1016/j.conb.2014.02.006 24608162

32. Kullander K, Klein R. Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol. 2002;3: 475–486. doi: 10.1038/nrm856 12094214

33. Niethamer TK, Bush JO. Getting direction(s): The Eph/ephrin signaling system in cell positioning. Dev Biol. 2019;447: 42–57. doi: 10.1016/j.ydbio.2018.01.012 29360434

34. Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol. 2005;6: 462–475. doi: 10.1038/nrm1662 15928710

35. Pasquale EB. Eph-ephrin bidirectional signaling in physiology and disease. Cell. 2008;133: 38–52. doi: 10.1016/j.cell.2008.03.011 18394988

36. Wilkinson DG. Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci. 2001;2: 155–164. doi: 10.1038/35058515 11256076

37. Wieland I, Makarov R, Reardon W, Tinschert S, Goldenberg A, Thierry P, et al. Dissecting the molecular mechanisms in craniofrontonasal syndrome: differential mRNA expression of mutant EFNB1 and the cellular mosaic. Eur J Hum Genet EJHG. 2008;16: 184–191. doi: 10.1038/sj.ejhg.5201968 18043713

38. Twigg SRF, Matsumoto K, Kidd AMJ, Goriely A, Taylor IB, Fisher RB, et al. The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males. Am J Hum Genet. 2006;78: 999–1010. doi: 10.1086/504440 16685650

39. Twigg SRF, Babbs C, van den Elzen MEP, Goriely A, Taylor S, McGowan SJ, et al. Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes. Hum Mol Genet. 2013;22: 1654–1662. doi: 10.1093/hmg/ddt015 23335590

40. Babbs C, Stewart HS, Williams LJ, Connell L, Goriely A, Twigg SRF, et al. Duplication of the EFNB1 gene in familial hypertelorism: imbalance in ephrin-B1 expression and abnormal phenotypes in humans and mice. Hum Mutat. 2011;32: 930–938. doi: 10.1002/humu.21521 21542058

41. Bush JO, Soriano P. Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph-ephrin boundaries. Genes Dev. 2010;24: 2068–2080. doi: 10.1101/gad.1963210 20844017

42. Compagni A, Logan M, Klein R, Adams RH. Control of skeletal patterning by ephrinB1-EphB interactions. Dev Cell. 2003;5: 217–30. doi: 10.1016/s1534-5807(03)00198-9 12919674

43. Niethamer TK, Larson AR, O’Neill AK, Bershteyn M, Hsiao EC, Klein OD, et al. EPHRIN-B1 Mosaicism Drives Cell Segregation in Craniofrontonasal Syndrome hiPSC-Derived Neuroepithelial Cells. Stem Cell Rep. 2017;8: 529–537. doi: 10.1016/j.stemcr.2017.01.017 28238796

44. O’Neill AK, Kindberg AA, Niethamer TK, Larson AR, Ho H-YH, Greenberg ME, et al. Unidirectional Eph/ephrin signaling creates a cortical actomyosin differential to drive cell segregation. J Cell Biol. 2016;215: 217–229. doi: 10.1083/jcb.201604097 27810913

45. Percival CJ, Green R, Marcucio R, Hallgrímsson B. Surface landmark quantification of embryonic mouse craniofacial morphogenesis. BMC Dev Biol. 2014;14: 31. doi: 10.1186/1471-213X-14-31 25059626

46. Kwee ML, Lindhout D. Frontonasal dysplasia, coronal cranisoynostosis, pre- and postaxial polydactyly and split nails: a new autosomal dominant mutant with reduced penetrance and varibale expression? Clin Genet. 1983;24: 200–205. doi: 10.1111/j.1399-0004.1983.tb02240.x 6627724

47. Hadjantonakis AK, Gertsenstein M, Ikawa M, Okabe M, Nagy A. Non-invasive sexing of preimplantation stage mammalian embryos. Nat Genet. 1998;19: 220–2. doi: 10.1038/893 9662390

48. Hadjantonakis AK, Cox LL, Tam PP, Nagy A. An X-linked GFP transgene reveals unexpected paternal X-chromosome activity in trophoblastic giant cells of the mouse placenta. Genesis. 2001;29: 133–40. doi: 10.1002/gene.1016 11252054

49. Inoue Y, Sakamoto Y, Sugimoto M, Inagaki H, Boda H, Miyata M, et al. A Family with Craniofrontonasal Syndrome: The First Report of Familial Cases of Craniofrontonasal Syndrome with Bilateral Cleft Lip and Palate. Cleft Palate-Craniofacial J Off Publ Am Cleft Palate-Craniofacial Assoc. 2018;55: 1026–1029. doi: 10.1597/15-347 28140668

50. Shotelersuk V, Siriwan P, Ausavarat S. A novel mutation in EFNB1, probably with a dominant negative effect, underlying craniofrontonasal syndrome. Cleft Palate-Craniofacial J Off Publ Am Cleft Palate-Craniofacial Assoc. 2006;43: 152–154. doi: 10.1597/05-014.1 16526919

51. Dougherty KJ, Zagoraiou L, Satoh D, Rozani I, Doobar S, Arber S, et al. Locomotor Rhythm Generation Linked to the Output of Spinal Shox2 Excitatory Interneurons. Neuron. 2013;80: 920–933. doi: 10.1016/j.neuron.2013.08.015 24267650

52. Yu L, Gu S, Alappat S, Song Y, Yan M, Zhang X, et al. Shox2-deficient mice exhibit a rare type of incomplete clefting of the secondary palate. Dev Camb Engl. 2005;132: 4397–4406. doi: 10.1242/dev.02013 16141225

53. Arvanitis DN, Béhar A, Tryoen-Tóth P, Bush JO, Jungas T, Vitale N, et al. Ephrin B1 maintains apical adhesion of neural progenitors. Development. 2013;140: 2082–2092. doi: 10.1242/dev.088203 23578932

54. Jones NC, Lynn ML, Gaudenz K, Sakai D, Aoto K, Rey JP, et al. Prevention of the neurocristopathy Treacher Collins syndrome through inhibition of p53 function. Nat Med. 2008;14: 125–33. doi: 10.1038/nm1725 18246078

55. Sakai D, Dixon J, Achilleos A, Dixon M, Trainor PA. Prevention of Treacher Collins syndrome craniofacial anomalies in mouse models via maternal antioxidant supplementation. Nat Commun. 2016;7: 10328. doi: 10.1038/ncomms10328 26792133

56. Takashima Y, Era T, Nakao K, Kondo S, Kasuga M, Smith AG, et al. Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell. 2007;129: 1377–1388. doi: 10.1016/j.cell.2007.04.028 17604725

57. Blits-Huizinga CT, Nelersa CM, Malhotra A, Liebl DJ. Ephrins and their receptors: binding versus biology. IUBMB Life. 2004;56: 257–265. doi: 10.1080/15216540412331270076 15370889

58. Dravis C, Henkemeyer M. Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues. Dev Biol. 2011;355: 138–151. doi: 10.1016/j.ydbio.2011.04.020 21539827

59. Orioli D, Henkemeyer M, Lemke G, Klein R, Pawson T. Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. EMBO J. 1996;15: 6035–6049. 8947026

60. Risley M, Garrod D, Henkemeyer M, McLean W. EphB2 and EphB3 forward signalling are required for palate development. Mech Dev. 2009;126: 230–239. doi: 10.1016/j.mod.2008.10.009 19032981

61. Henkemeyer M, Orioli D, Henderson JT, Saxton TM, Roder J, Pawson T, et al. Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell. 1996;86: 35–46. doi: 10.1016/s0092-8674(00)80075-6 8689685

62. Williams SE, Mann F, Erskine L, Sakurai T, Wei S, Rossi DJ, et al. Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron. 2003;39: 919–935. doi: 10.1016/j.neuron.2003.08.017 12971893

63. Rollnick B, Day D, Tissot R, Kaye C. A pedigree possible evidence for the metabolic interference hypothesis. Am J Hum Genet. 1981;33: 823–826. 7294029

64. Taylor HB, Khuong A, Wu Z, Xu Q, Morley R, Gregory L, et al. Cell segregation and border sharpening by Eph receptor–ephrin-mediated heterotypic repulsion. J R Soc Interface. 2017;14: 20170338. doi: 10.1098/rsif.2017.0338 28747399

65. Poliakov A, Cotrina ML, Pasini A, Wilkinson DG. Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway. J Cell Biol. 2008;183: 933–47. doi: 10.1083/jcb.200807151 19047466

66. Solanas G, Cortina C, Sevillano M, Batlle E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol. 2011;13: 1100–7. doi: 10.1038/ncb2298 21804545

67. Bush JO, Soriano P. Eph/ephrin signaling: genetic, phosphoproteomic, and transcriptomic approaches. Semin Cell Dev Biol. 2012;23: 26–34. doi: 10.1016/j.semcdb.2011.10.018 22040918

68. Davy A, Soriano P. Ephrin signaling in vivo: look both ways. Dev Dyn Off Publ Am Assoc Anat. 2005;232: 1–10. doi: 10.1002/dvdy.20200 15580616

69. Agrawal P, Wang M, Kim S, Lewis AE, Bush JO. Embryonic expression of EphA receptor genes in mice supports their candidacy for involvement in cleft lip and palate. Dev Dyn Off Publ Am Assoc Anat. 2014. doi: 10.1002/dvdy.24170 25073978

70. North HA, Zhao X, Kolk SM, Clifford MA, Ziskind DM, Donoghue MJ. Promotion of proliferation in the developing cerebral cortex by EphA4 forward signaling. Dev Camb Engl. 2009;136: 2467–2476. doi: 10.1242/dev.034405 19542359

71. Skare Ø, Gjessing HK, Gjerdevik M, Haaland ØA, Romanowska J, Lie RT, et al. A new approach to chromosome-wide analysis of X-linked markers identifies new associations in Asian and European case-parent triads of orofacial clefts. PLOS ONE. 2017;12: e0183772. doi: 10.1371/journal.pone.0183772 28877219

72. Lewandoski M, Meyers EN, Martin GR. Analysis of Fgf8 gene function in vertebrate development. Cold Spring Harb Symp Quant Biol. 1997;62: 159–168. 9598348

73. Matsuoka T, Ahlberg PE, Kessaris N, Iannarelli P, Dennehy U, Richardson WD, et al. Neural crest origins of the neck and shoulder. Nature. 2005;436: 347–355. doi: 10.1038/nature03837 16034409

74. Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L. A global double-fluorescent Cre reporter mouse. Genes N Y N 2000. 2007;45: 593–605. doi: 10.1002/dvg.20335 17868096

75. Adams DC, Otárola‐Castillo E. geomorph: an r package for the collection and analysis of geometric morphometric shape data. Methods Ecol Evol. 2013;4: 393–399. doi: 10.1111/2041-210X.12035

Štítky
Genetika Reprodukční medicína

Článek vyšel v časopise

PLOS Genetics


2020 Číslo 2

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Kurzy Doporučená témata Časopisy
Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se

VIRTUÁLNÍ ČEKÁRNA ČR Jste praktický lékař nebo pediatr? Zapojte se! Jste praktik nebo pediatr? Zapojte se!

×