Mutations in (Hhat) Perturb Hedgehog Signaling, Resulting in Severe Acrania-Holoprosencephaly-Agnathia Craniofacial Defects

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Holoprosencephaly (HPE) is a failure of the forebrain to bifurcate and is the most common structural malformation of the embryonic brain. Mutations in SHH underlie most familial (17%) cases of HPE; and, consistent with this, Shh is expressed in midline embryonic cells and tissues and their derivatives that are affected in HPE. It has long been recognized that a graded series of facial anomalies occurs within the clinical spectrum of HPE, as HPE is often found in patients together with other malformations such as acrania, anencephaly, and agnathia. However, it is not known if these phenotypes arise through a common etiology and pathogenesis. Here we demonstrate for the first time using mouse models that Hedgehog acyltransferase (Hhat) loss-of-function leads to holoprosencephaly together with acrania and agnathia, which mimics the severe condition observed in humans. Hhat is required for post-translational palmitoylation of Hedgehog (Hh) proteins; and, in the absence of Hhat, Hh secretion from producing cells is diminished. We show through downregulation of the Hh receptor Ptch1 that loss of Hhat perturbs long-range Hh signaling, which in turn disrupts Fgf, Bmp and Erk signaling. Collectively, this leads to abnormal patterning and extensive apoptosis within the craniofacial primordial, together with defects in cartilage and bone differentiation. Therefore our work shows that Hhat loss-of-function underscrores HPE; but more importantly it provides a mechanism for the co-occurrence of acrania, holoprosencephaly, and agnathia. Future genetic studies should include HHAT as a potential candidate in the etiology and pathogenesis of HPE and its associated disorders.

Vyšlo v časopise: Mutations in (Hhat) Perturb Hedgehog Signaling, Resulting in Severe Acrania-Holoprosencephaly-Agnathia Craniofacial Defects. PLoS Genet 8(10): e32767. doi:10.1371/journal.pgen.1002927
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002927

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Zdroje

1. BelloniE, MuenkeM, RoesslerE, TraversoG, Siegel-BarteltJ, et al. (1996) Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genetics 14: 353–356.

2. RoesslerE, BelloniE, GaudenzK, JayP, BertaP, et al. (1996) Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14: 357–360.

3. MuenkeM, BeachyPA (2000) Genetics of ventral forebrain development and holoprosencephaly. Curr Opin Genet Dev 10: 262–269.

4. WallisD, MuenkeM (2000) Mutations in holoprosencephaly. Hum Mutat 16: 99–108.

5. DeMyer ME (1977) Holoprosencephaly (cyclopia-arhinencephaly); Vinken PJ, Bruyn GW, editors. Amerstam: North-Hollan.

6. DemyerW, ZemanW, PalmerCG (1964) The Face Predicts the Brain: Diagnostic Significance of Median Facial Anomalies for Holoprosencephaly (Arhinencephaly). Pediatrics 34: 256–263.

7. DemyerW, ZemanW (1963) Alobar holoprosencephaly (arhinencephaly) with median cleft lip and palate: clinical, electroencephalographic and nosologic considerations. Confin Neurol 23: 1–36.

8. MartinRA, JonesKL, BenirschkeK (1996) Absence of the lateral philtral ridges: a clue to the structural basis of the philtrum. Am J Med Genet 65: 117–123.

9. CohenMMJr, ShiotaK (2002) Teratogenesis of holoprosencephaly. Am J Med Genet 109: 1–15.

10. AotoK, YayoiS, HigashiyamaD, ShiotaK, MotoyamaJ (2008) Fetal ethanol exposure activates protein kinase a and impairs Shh expression in prechordal mesendoderm cells in the pathogenesis of holoprosencephaly. Birth Defects Res A Clin Mol Teratol

11. BarrMJr, HansonJW, CurreyK, SharpS, TorielloH, et al. (1983) Holoprosencephaly in infants of diabetic mothers. J Pediatr 102: 565–568.

12. PorterJA, EkkerSC, ParkWJ, von KesslerDP, YoungKE, et al. (1996) Hedgehog patterning activity: role of a lipophilic modification mediated by the carboxy-terminal autoprocessing domain. Cell 86: 21–34.

13. PorterJA, YoungKE, BeachyPA (1996) Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255–259.

14. PepinskyRB, ZengC, WenD, RayhornP, BakerD, et al. (1998) Identification of a palmitic acid-modified form of human Sonic hedgehog. Journal of Biological Chemistry 273: 14037–14045.

15. NelsonDK, WilliamsT (2004) Frontonasal process-specific disruption of AP-2alpha results in postnatal midfacial hypoplasia, vascular anomalies, and nasal cavity defects. Dev Biol 267: 72–92.

16. ZhangJ, WilliamsT (2003) Identification and regulation of tissue-specific cis-acting elements associated with the human AP-2alpha gene. Dev Dyn 228: 194–207.

17. ChaiY, MaxsonREJr (2006) Recent advances in craniofacial morphogenesis. Dev Dyn 235: 2353–2375.

18. KronenbergHM (2003) Developmental regulation of the growth plate. Nature 423: 332–336.

19. ChiangC, LitingtungY, LeeE, YoungKE, CordenJL, et al. (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383: 407–413.

20. GoodrichLV, MilenkovicL, HigginsKM, ScottMP (1997) Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277: 1109–1113.

21. CostantiniF, LacyE (1981) Introduction of a rabbit beta-globin gene into the mouse germ line. Nature 294: 92–94.

22. JaenischR (1988) Transgenic animals. Science 240: 1468–1474.

23. HeaneyJD, BronsonSK (2006) Artificial chromosome-based transgenes in the study of genome function. Mamm Genome 17: 791–807.

24. TaylorFR, WenD, GarberEA, CarmilloAN, BakerDP, et al. (2001) Enhanced potency of human Sonic hedgehog by hydrophobic modification. Biochemistry 40: 4359–4371.

25. ChenMH, LiYJ, KawakamiT, XuSM, ChuangPT (2004) Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev 18: 641–659.

26. AmanaiK, JiangJ (2001) Distinct roles of Central missing and Dispatched in sending the Hedgehog signal. Development 128: 5119–5127.

27. ChamounZ, MannRK, NellenD, von KesslerDP, BellottoM, et al. (2001) Skinny hedgehog, an acyltransferase required for palmitoylation and activity of the hedgehog signal. Science 293: 2080–2084.

28. LeeJD, TreismanJE (2001) Sightless has homology to transmembrane acyltransferases and is required to generate active Hedgehog protein. Curr Biol 11: 1147–1152.

29. MicchelliCA, TheI, SelvaE, MogilaV, PerrimonN (2002) Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling. Development 129: 843–851.

30. MacdonaldR, BarthKA, XuQ, HolderN, MikkolaI, et al. (1995) Midline signalling is required for Pax gene regulation and patterning of the eyes. Development 121: 3267–3278.

31. DaleJ, VesqueC, LintsT, SampathK, FurleyA, et al. (1997) Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Cell 90: 257–269.

32. St-JacquesB, HammerschmidtM, McMahonAP (1999) Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13: 2072–2086.

33. LentonK, JamesAW, ManuA, BrugmannSA, BirkerD, et al. (2011) Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling. Genesis 49: 784–796.

34. Le Douarin N, Kalcheim C (1999) The Neural Crest; Bard J, Barlow P, Kirk D, editors: Cambridge Univesity Press.

35. NodenD (1978) The control of avian cephalic neural crest cytodifferentiation I. skeletal and connective tissues. Devl Biol 67: 296–312.

36. JeongJ, MaoJ, TenzenT, KottmannAH, McMahonAP (2004) Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev 18: 937–951.

37. AhlgrenSC, Bronner-FraserM (1999) Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death. Curr Biol 9: 1304–1314.

38. Moore-ScottBA, ManleyNR (2005) Differential expression of Sonic hedgehog along the anterior-posterior axis regulates patterning of pharyngeal pouch endoderm and pharyngeal endoderm-derived organs. Dev Biol 278: 323–335.

39. YamagishiC, YamagishiH, MaedaJ, TsuchihashiT, IveyK, et al. (2006) Sonic hedgehog is essential for first pharyngeal arch development. Pediatr Res 59: 349–354.

40. Larson WJ (1993) Essentials of Human Embryology: Churchill Livingstone Inc.

41. AhlgrenSC, ThakurV, Bronner-FraserM (2002) Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sci U S A 99: 10476–10481.

42. LiuW, SeleverJ, MuraliD, SunX, BruggerSM, et al. (2005) Threshold-specific requirements for Bmp4 in mandibular development. Dev Biol 283: 282–293.

43. ChangH, LiQ, MoraesRC, LewisMT, HamelPA (2010) Activation of Erk by sonic hedgehog independent of canonical hedgehog signalling. Int J Biochem Cell Biol 42: 1462–1471.

44. BritoJM, TeilletMA, Le DouarinNM (2006) An early role for sonic hedgehog from foregut endoderm in jaw development: ensuring neural crest cell survival. Proc Natl Acad Sci U S A 103: 11607–11612.

45. HuD, MarcucioRS (2009) A SHH-responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm. Development 136: 107–116.

46. MarcucioRS, CorderoDR, HuD, HelmsJA (2005) Molecular interactions coordinating the development of the forebrain and face. Dev Biol 284: 48–61.

47. CrossleyPH, MartinGR (1995) The mouse FGF-8 gene encodes a family of polypeptides expressed in regions that direct outgrowth and patterning in the developing embryo. Development 121: 439–451.

48. BennettJH, HuntP, ThorogoodP (1995) Bone morphogenetic protein-2 and -4 expression during murine orofacial development. Arch Oral Biol 40: 847–854.

49. TrumppA, DepewMJ, RubensteinJL, BishopJM, MartinGR (1999) Cre-mediated gene inactivation demonstrates that FGF8 is required for cell survival and patterning of the first branchial arch. Genes Dev 13: 3136–3148.

50. TuckerAS, YamadaG, GrigoriouM, PachnisV, SharpePT (1999) Fgf-8 determines rostral-caudal polarity in the first branchial arch. Development 126: 51–61.

51. HaworthKE, WilsonJM, GrevellecA, CobourneMT, HealyC, et al. (2007) Sonic hedgehog in the pharyngeal endoderm controls arch pattern via regulation of Fgf8 in head ectoderm. Dev Biol 303: 244–258.

52. FengW, LeachSM, TipneyH, PhangT, GeraciM, et al. (2009) Spatial and temporal analysis of gene expression during growth and fusion of the mouse facial prominences. PLoS ONE 4: e8066 doi:10.1371/journal.pone.0008066.

53. BitgoodMJ, McMahonAP (1995) Hedgehog and Bmp genes are coexpressed at many diverse sites of cell-cell interaction in the mouse embryo. Dev Biol 172: 126–138.

54. KronmillerJE, NguyenT (1996) Spatial and temporal distribution of Indian hedgehog mRNA in the embryonic mouse mandible. Arch Oral Biol 41: 577–583.

55. SorianoP (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21: 70–71.

56. JiangX, RowitchDH, SorianoP, McMahonAP, SucovHM (2000) Fate of the mammalian cardiac neural crest. Development 127: 1607–1616.

57. ChaiY, JiangX, ItoY, BringasPJr, HanJ, et al. (2000) Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 127: 1671–1679.

58. Nagy A, Gertsenstein M, Vintersten K, Behringer RR (2003) Manipulating the mouse embryo. Cold Spring Harbor: Cold Spring Harbor Laboratory.