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Holoprosencephaly: new models, new insights

Published online by Cambridge University Press:  24 September 2007

Robert S. Krauss
Robert S. Krauss
Affiliation:
Department of Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, New York, NY 10029, USA. Tel: +1 212 241 2177; Fax: +2 212 860 9279; E-mail: Robert.Krauss@mssm.edu
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Abstract

Holoprosencephaly (HPE) is a common congenital malformation that is characterised by a failure to divide the forebrain into left and right hemispheres and is usually accompanied by defects in patterning of the midline of the face. HPE exists in inherited, autosomal dominant (familial) forms and mutation-associated sporadic forms, but environmental factors are also implicated. There are several features of HPE that are not well understood, including the extremely variable clinical presentation, even among obligate carriers of familial mutations, and the restriction of structural anomalies to the ventral anterior midline, despite association with defects in signal transduction pathways that regulate development of many additional body structures. The new animal models described in this review may help unravel these puzzles. Furthermore, these model systems suggest that human HPE arises from a complex interaction between the timing and strength of developmental signalling pathways, genetic variation and exposure to environmental agents.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 9 , Issue 26 , September 2007 , pp. 1 - 17
Copyright
Copyright © Cambridge University Press 2007

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References

References

1Muenke, M. and Beachy, P.A. (2001) Holoprosencephaly. In The Metabolic & Molecular Bases of Inherited Disease (Eighth Edition, IV) (Scriver, C.R. et al. , eds), pp. 6203-6230, McGraw-Hill, New YorkGoogle Scholar
2Yamada, S. et al. (2004) Phenotypic variability in human embryonic holoprosencephaly in the Kyoto Collection. Birth Defects Res. Part A Clin Mol Teratol 70, 495-508CrossRefGoogle ScholarPubMed
3Cohen, M.M. Jr. (2006) Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res. Part A Clin Mol Teratol 76, 658-673Google Scholar
4Dubourg, C. et al. (2007) Holoprosencephaly. Orphanet J Rare Dis 2, 8CrossRefGoogle ScholarPubMed
5Simon, E.M. et al. (2002) The middle interhemispheric variant of holoprosencephaly. AJNR Am J Neuroradiol 23, 151-156Google ScholarPubMed
6Ming, J.E. and Muenke, M. (2002) Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 71, 1017-1032CrossRefGoogle ScholarPubMed
7DeMyer, W.E. (1964) The face predicts the brain: Diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 34, 256-263CrossRefGoogle ScholarPubMed
8Fuccillo, M., Joyner, A.L. and Fishell, G. (2006) Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat Rev Neurosci 7, 772-783CrossRefGoogle ScholarPubMed
9Hebert, J.M. (2005) Unraveling the molecular pathways that regulate early telencephalon development. Curr Top Dev Biol 69, 17-37CrossRefGoogle ScholarPubMed
10Lupo, G., Harris, W.A. and Lewis, K.E. (2006) Mechanisms of ventral patterning in the vertebrate nervous system. Nat Rev Neurosci 7, 103-114CrossRefGoogle ScholarPubMed
11Monuki, E.S. and Walsh, C.A. (2001) Mechanisms of cerebral cortical patterning in mice and humans. Nat Neurosci 4, Suppl 1199-1206CrossRefGoogle ScholarPubMed
12Rallu, M., Corbin, J.G. and Fishell, G. (2002) Parsing the prosencephalon. Nat Rev Neurosci 3, 943-951CrossRefGoogle ScholarPubMed
13Wilson, S.W. and Houart, C. (2004) Early steps in the development of the forebrain. Dev Cell 6, 167-181CrossRefGoogle ScholarPubMed
14Rubenstein, J.L. and Beachy, P.A. (1998) Patterning of the embryonic forebrain. Curr Opin Neurobiol 8, 18-26CrossRefGoogle ScholarPubMed
15Lowe, L.A., Yamada, S. and Kuehn, M.R. (2001) Genetic dissection of nodal function in patterning the mouse embryo. Development 128, 1831-1843CrossRefGoogle ScholarPubMed
16Shen, M.M. (2007) Nodal signaling: developmental roles and regulation. Development 134, 1023-1034Google Scholar
17Weng, W. and Stemple, D.L. (2003) Nodal signaling and vertebrate germ layer formation. Birth Defects Res C Embryo Today 69, 325-332Google Scholar
18Chen, X. et al. (1997) Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85-89Google Scholar
19Yamamoto, M. et al. (2001) The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior-posterior patterning and node formation in the mouse. Genes Dev 15, 1242-1256CrossRefGoogle ScholarPubMed
20Chu, J. et al. (2005) Non-cell-autonomous role for Cripto in axial midline formation during vertebrate embryogenesis. Development 132, 5539-5551CrossRefGoogle ScholarPubMed
21de la Cruz, J.M. et al. (2002) A loss-of-function mutation in the CFC domain of TDGF1 is associated with human forebrain defects. Hum Genet 110, 422-428Google Scholar
22Heyer, J. et al. (1999) Postgastrulation Smad2-deficient embryos show defects in embryo turning and anterior morphogenesis. Proc Natl Acad Sci U S A 96, 12595-12600CrossRefGoogle ScholarPubMed
23Nomura, M. and Li, E. (1998) Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393, 786-790CrossRefGoogle ScholarPubMed
24Pogoda, H.M. et al. (2000) The zebrafish forkhead transcription factor FoxH1/Fast1 is a modulator of nodal signaling required for organizer formation. Curr Biol 10, 1041-1049Google Scholar
25Sampath, K. et al. (1998) Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 395, 185-189CrossRefGoogle ScholarPubMed
26Sirotkin, H.I. et al. (2000) fast1 is required for the development of dorsal axial structures in zebrafish. Curr Biol 10, 1051-1054CrossRefGoogle ScholarPubMed
27Song, J. et al. (1999) The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev Biol 213, 157-169Google Scholar
28Zhang, J., Talbot, W.S. and Schier, A.F. (1998) Positional cloning identifies zebrafish one-eyed pinhead as a permissive EGF-related ligand required during gastrulation. Cell 92, 241-251CrossRefGoogle ScholarPubMed
29Huangfu, D. and Anderson, K.V. (2006) Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 133, 3-14CrossRefGoogle ScholarPubMed
30Wang, Y., McMahon, A.P. and Allen, B.L. (2007) Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol 19, 159-165Google Scholar
31Chen, M.H. et al. (2004) Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev 18, 641-659Google Scholar
32Chiang, C. et al. (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407-413Google Scholar
33Dubourg, C. et al. (2004) Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: Mutation review and genotype-phenotype correlations. Hum Mutat 24, 43-51CrossRefGoogle ScholarPubMed
34Ma, Y. et al. (2002) Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111, 63-75CrossRefGoogle ScholarPubMed
35Ming, J.E. et al. (2002) Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 110, 297-301CrossRefGoogle ScholarPubMed
36Nanni, L. et al. (1999) The mutational spectrum of the Sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet 8, 2479-2488CrossRefGoogle Scholar
37Rahimov, F. et al. (2006) GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum? Am J Med Genet A 140, 2571-2576CrossRefGoogle ScholarPubMed
38Ribeiro, L.A., Murray, J.C. and Richieri-Costa, A. (2006) PTCH mutations in four Brazilian patients with holoprosencephaly and in one with holoprosencephaly-like features and normal MRI. Am J Med Genet A 140, 2584-2586Google Scholar
39Roessler, E. et al. (1996) Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14, 357-360Google Scholar
40Roessler, E. et al. (2003) Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features. Proc Natl Acad Sci U S A 100, 13424-13429CrossRefGoogle ScholarPubMed
41Zhang, X.M., Ramalho-Santos, M. and McMahon, A.P. (2001) Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 106, 781-792Google Scholar
42Koebernick, K. and Pieler, T. (2002) Gli-type zinc finger proteins as bipotential transducers of Hedgehog signaling. Differentiation 70, 69-76Google Scholar
43Sasaki, H. et al. (1999) Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126, 3915-3924Google Scholar
44Wang, B., Fallon, J.F. and Beachy, P.A. (2000) Hedgehog-regulated processing of Gli3 produces an anterior/posterior repressor gradient in the developing vertebrate limb. Cell 100, 423-434Google Scholar
45Grove, E.A. et al. (1998) The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3-deficient mice. Development 125, 2315-2325CrossRefGoogle ScholarPubMed
46Tole, S., Ragsdale, C.W. and Grove, E.A. (2000) Dorsoventral patterning of the telencephalon is disrupted in the mouse mutant extra-toes. Dev Biol 217, 254-265Google Scholar
47Rallu, M. et al. (2002) Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling. Development 129, 4963-4974Google Scholar
48Gutin, G. et al. (2006) FGF signalling generates ventral telencephalic cells independently of SHH. Development 133, 2937-2946CrossRefGoogle ScholarPubMed
49Storm, E.E. et al. (2006) Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 133, 1831-1844CrossRefGoogle ScholarPubMed
50Aoto, K. et al. (2002) Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 251, 320-332Google Scholar
51Golden, J.A. et al. (1999) Ectopic bone morphogenetic proteins 5 and 4 in the chicken forebrain lead to cyclopia and holoprosencephaly. Proc Natl Acad Sci U S A 96, 2439-2444Google Scholar
52Dale, J.K. et al. (1997) Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Cell 90, 257-269CrossRefGoogle ScholarPubMed
53Li, H. et al. (1997) A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate. Development 124, 603-615Google Scholar
54Pera, E.M. and Kessel, M. (1997) Patterning of the chick forebrain anlage by the prechordal plate. Development 124, 4153Google Scholar
55Varga, Z.M., Wegner, J. and Westerfield, M. (1999) Anterior movement of ventral diencephalic precursors separates the primordial eye field in the neural plate and requires cyclops. Development 126, 5533-5546Google Scholar
56Helms, J.A., Cordero, D. and Tapadia, M.D. (2005) New insights into craniofacial morphogenesis. Development 132, 851-861Google Scholar
57Hu, D. and Helms, J.A. (1999) The role of Sonic hedgehog in normal and abnormal craniofacial morphogenesis. Development 126, 4873-4884CrossRefGoogle ScholarPubMed
58Cordero, D. et al. (2004) Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes. J Clin Invest 114, 485-494CrossRefGoogle ScholarPubMed
59Cohen, M.M. Jr. and Shiota, K. (2002) Teratogenesis of holoprosencephaly. Am J Med Genet 109, 1-15CrossRefGoogle ScholarPubMed
60Roessler, E. and Muenke, M. (1998) Holoprosencephaly: a paradigm for the complex genetics of brain development. J Inherit Metab Dis 21, 481-497Google Scholar
61Bendavid, C. et al. (2006) Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Mun Genet 119, 1-8Google Scholar
62Bendavid, C. et al. (2006) Multicolour FISH and quantitative PCR can detect submicroscopic deletions in holoprosencephaly patients with a normal karyotype. J Med Genet 43, 496-500Google Scholar
63El-Jaick, K.B. et al. (2007) Functional analysis of mutations in TGIF associated with holoprosencephaly. Mol Genet Metab 90, 97-111Google Scholar
64Maity, T., Fuse, N. and Beachy, P.A. (2005) Molecular mechanisms of Sonic hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci U S A 102, 17026-17031Google Scholar
65Schell-Apacik, C. et al. (2003) SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum Genet 113, 170-177Google Scholar
66Traiffort, E. et al. (2004) Functional characterization of sonic hedgehog mutations associated with holoprosencephaly. J Biol Chem 279, 42889-42897Google Scholar
67Cohen, M.M. Jr. (1989) Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology 40, 211-235Google Scholar
68Barr, M.J. et al. (1983) Holoprosencephaly in infants of diabetic mothers. J Pediatr 102, 565-568Google Scholar
69Croen, L.A., Shaw, G.M. and Lammer, E.J. (2000) Risk factors for cytogenetically normal holoprosencephaly in California: a population-based case-control study. Am J Med Genet 90, 320-325Google Scholar
70Ahlgren, S.C., Thakur, V. and Bronner-Fraser, M. (2002) Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sci U S A 99, 10476-10481Google Scholar
71Li, Y.X. et al. (2007) Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling. Lab Invest 87, 231-240Google Scholar
72Kelley, R.L. et al. (1996) Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: does abnormal cholesterol metabolism affect the function of Sonic Hedgehog? Am J Med Genet 66, 4478-4484Google Scholar
73Edison, R.J. and Muenke, M. (2004) Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 131, 287-298Google Scholar
74Cooper, M.K. et al. (2003) A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 33, 508-513Google Scholar
75Haas, D. et al. (2007) Abnormal sterol metabolism in holoprosencephaly: studies in cultured lymphoblasts. J Med Genet 44, 298-305CrossRefGoogle ScholarPubMed
76Allen, B.L., Tenzen, T. and McMahon, A.P. (2007) The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev 21, 1244-1257Google Scholar
77Martinelli, D.C. and Fan, C.M. (2007) Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21, 1231-1243CrossRefGoogle ScholarPubMed
78Seppala, M. et al. (2007) Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest 117, 1575-1584Google Scholar
79Cole, F. and Krauss, R.S. (2003) Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon. Curr Biol 13, 411-415Google Scholar
80Zhang, W. et al. (2006) Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 10, 657-665Google Scholar
81Petryk, A. et al. (2004) The mammalian twisted gastrulation gene functions in foregut and craniofacial development. Dev Biol 267, 374-386CrossRefGoogle ScholarPubMed
82Zakin, L. and De Robertis, E.M. (2004) Inactivation of mouse Twisted gastrulation reveals its role in promoting Bmp4 activity during forebrain development. Development 131, 413-424CrossRefGoogle ScholarPubMed
83Anderson, R.M. et al. (2002) Chordin and noggin promote organizing centers of forebrain development in the mouse. Development 129, 4975-4987Google Scholar
84Bachiller, D. et al. (2000) The organizer factors Chordin and Noggin are required for mouse forebrain development. Nature 403, 658-661Google Scholar
85Ohkubo, Y., Chiang, C. and Rubenstein, J.L. (2002) Coordinate regulation and synergistic actions of BMP4, SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles. Neuroscience 111, 1-17CrossRefGoogle ScholarPubMed
86Bartholin, L. et al. (2006) TGIF inhibits retinoid signaling. Mol Cell Biol 26, 990-1001CrossRefGoogle ScholarPubMed
87Jin, J.Z. et al. (2006) Expression and functional analysis of Tgif during mouse midline development. Dev Dyn 235, 547-553CrossRefGoogle ScholarPubMed
88Shen, J. and Walsh, C.A. (2005) Targeted disruption of Tgif, the mouse ortholog of a human holoprosencephaly gene, does not result in holoprosencephaly in mice. Mol Cell Biol 25, 3639-3647Google Scholar
89Mar, L. and Hoodless, P.A. (2006) Embryonic fibroblasts from mice lacking Tgif were defective in cell cycling. Mol Cell Biol 26, 4302-4310Google Scholar
90Kuang, C. et al. (2006) Intragenic deletion of Tgif causes defects in brain development. Hum Mol Genet 15, 3508-3519Google Scholar
91Ding, J. et al. (1998) Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature 395, 702-707CrossRefGoogle ScholarPubMed
92Marcucio, R.S. et al. (2005) Molecular interactions coordinating the development of the forebrain and face. Dev Biol 284, 48-61Google Scholar
93Lanoue, L. et al. (1997) Limb, genital, CNS, and facial malformations result from gene/environment-induced cholesterol deficiency: further evidence for a link to sonic hedgehog. Am J Med Genet 73, 24-313.0.CO;2-P>CrossRefGoogle ScholarPubMed
94Ingham, P.W. and Placzek, M. (2006) Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 7, 841-850CrossRefGoogle ScholarPubMed
95McMahon, A.P., Ingham, P.W. and Tabin, C.J. (2003) Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 53, 1-114Google Scholar
96Tenzen, T. et al. (2006) The cell surface membrane proteins Cdo and Boc are components and targets of the hedgehog signaling pathway and feedback network in mice. Dev Cell 10, 647-656Google Scholar
97Okada, A. et al. (2006) Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444, 369-373Google Scholar
98Jeong, Y. et al. (2006) A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers. Development 133, 761-772Google Scholar
99Lettice, L.A. et al. (2003) A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 12, 1725-1735Google Scholar
100Hayhurst, M. and McConnell, S.K. (2003) Mouse models of holoprosencephaly. Curr Opin Neurol 16, 135-141Google Scholar
101Furuta, Y., Piston, D.W. and Hogan, B.L. (1997) Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. Development 124, 2203-2212Google Scholar
102Cheng, X. et al. (2006) Central roles of the roof plate in telencephalic development and holoprosencephaly. J Neurosci 26, 7640-7649CrossRefGoogle ScholarPubMed
103Brown, S.A. et al. (1998) Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet 20, 180-183CrossRefGoogle ScholarPubMed
104Nagai, T. et al. (2000) Zic2 regulates the kinetics of neurulation. Proc Natl Acad Sci U S A 97, 1618-1623Google Scholar
105Nagai, T. et al. (1997) The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation. Dev Biol 182, 299-313CrossRefGoogle ScholarPubMed
106Huang, X., Litingtung, Y. and Chiang, C. (2007) Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly. Hum Mol Genet 16, 1454-1468Google Scholar
107Chen, L. et al. (2006) Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc Natl Acad Sci U S A 103, 16520-16525Google Scholar
108Varlet, I. et al. (1997) Nodal signaling and axis formation in the mouse. Cold Spring Harb Symp Quant Biol 62, 105-113Google ScholarPubMed
109Jin, O. et al. (2001) Otx2 and HNF3β genetically interact in anterior patterning. Int J Dev Biol 45, 357-365Google ScholarPubMed
110Andersson, O. et al. (2006) Synergistic interaction between Gdf1 and Nodal during anterior axis development. Dev Biol 293, 370-381Google Scholar

Further reading, resources and contacts

Muenke, M. and Beachy, P.A. (2001) Holoprosencephaly. In The Metabolic & Molecular Bases of Inherited Disease (Scriver, C. R. et al. ed.), pp. 6203–6230. McGraw-Hill, New YorkGoogle Scholar
Yamada, S. et al. (2004) Phenotypic variability in human embryonic holoprosencephaly in the Kyoto Collection. Birth Defects Res Part A Clin Mol Teratol 70, 495–508Google Scholar
Cohen, M.M. Jr. (2006) Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res Part A Clin Mol Teratol 76, 658–673Google Scholar
Dubourg, C. et al. (2007) Holoprosencephaly. Orphanet J Rare Dis 2, 8CrossRefGoogle ScholarPubMed
Ming, J.E. and Muenke, M. (2002) Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 71, 1017–1032Google Scholar
http://www.ninds.nih.gov/disorders/holoprosencephaly/holoprosencephaly.htmGoogle Scholar
http://www.stanford.edu/group/hpe/Google Scholar