Skip to main content
×
Home
    • Aa
    • Aa

Holoprosencephaly: new models, new insights

  • Robert S. Krauss (a1)
Abstract
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.

Copyright
References
Hide All
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 York
2Yamada S. et al. (2004) Phenotypic variability in human embryonic holoprosencephaly in the Kyoto Collection. Birth Defects Res. Part A Clin Mol Teratol 70, 495-508
3Cohen M.M. Jr. (2006) Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res. Part A Clin Mol Teratol 76, 658-673
4Dubourg C. et al. (2007) Holoprosencephaly. Orphanet J Rare Dis 2, 8
5Simon E.M. et al. (2002) The middle interhemispheric variant of holoprosencephaly. AJNR Am J Neuroradiol 23, 151-156
6Ming J.E. and Muenke M. (2002) Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 71, 1017-1032
7DeMyer W.E. (1964) The face predicts the brain: Diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 34, 256-263
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, 772-783
9Hebert J.M. (2005) Unraveling the molecular pathways that regulate early telencephalon development. Curr Top Dev Biol 69, 17-37
10Lupo G., Harris W.A. and Lewis K.E. (2006) Mechanisms of ventral patterning in the vertebrate nervous system. Nat Rev Neurosci 7, 103-114
11Monuki E.S. and Walsh C.A. (2001) Mechanisms of cerebral cortical patterning in mice and humans. Nat Neurosci 4, Suppl 1199-1206
12Rallu M., Corbin J.G. and Fishell G. (2002) Parsing the prosencephalon. Nat Rev Neurosci 3, 943-951
13Wilson S.W. and Houart C. (2004) Early steps in the development of the forebrain. Dev Cell 6, 167-181
14Rubenstein J.L. and Beachy P.A. (1998) Patterning of the embryonic forebrain. Curr Opin Neurobiol 8, 18-26
15Lowe L.A., Yamada S. and Kuehn M.R. (2001) Genetic dissection of nodal function in patterning the mouse embryo. Development 128, 1831-1843
16Shen M.M. (2007) Nodal signaling: developmental roles and regulation. Development 134, 1023-1034
17Weng W. and Stemple D.L. (2003) Nodal signaling and vertebrate germ layer formation. Birth Defects Res C Embryo Today 69, 325-332
18Chen X. et al. (1997) Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85-89
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, 1242-1256
20Chu J. et al. (2005) Non-cell-autonomous role for Cripto in axial midline formation during vertebrate embryogenesis. Development 132, 5539-5551
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, 422-428
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, 12595-12600
23Nomura M. and Li E. (1998) Smad2 role in mesoderm formation, left-right patterning and craniofacial development. Nature 393, 786-790
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, 1041-1049
25Sampath K. et al. (1998) Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 395, 185-189
26Sirotkin H.I. et al. (2000) fast1 is required for the development of dorsal axial structures in zebrafish. Curr Biol 10, 1051-1054
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, 157-169
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, 241-251
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, 3-14
30Wang Y., McMahon A.P. and Allen B.L. (2007) Shifting paradigms in Hedgehog signaling. Curr Opin Cell Biol 19, 159-165
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, 641-659
32Chiang C. et al. (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407-413
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, 43-51
34Ma Y. et al. (2002) Hedgehog-mediated patterning of the mammalian embryo requires transporter-like function of dispatched. Cell 111, 63-75
35Ming J.E. et al. (2002) Mutations in PATCHED-1, the receptor for SONIC HEDGEHOG, are associated with holoprosencephaly. Hum Genet 110, 297-301
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, 2479-2488
37Rahimov F. et al. (2006) GLI2 mutations in four Brazilian patients: how wide is the phenotypic spectrum? Am J Med Genet A 140, 2571-2576
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, 2584-2586
39Roessler E. et al. (1996) Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 14, 357-360
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, 13424-13429
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, 781-792
42Koebernick K. and Pieler T. (2002) Gli-type zinc finger proteins as bipotential transducers of Hedgehog signaling. Differentiation 70, 69-76
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, 3915-3924
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, 423-434
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, 2315-2325
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, 254-265
47Rallu M. et al. (2002) Dorsoventral patterning is established in the telencephalon of mutants lacking both Gli3 and Hedgehog signaling. Development 129, 4963-4974
48Gutin G. et al. (2006) FGF signalling generates ventral telencephalic cells independently of SHH. Development 133, 2937-2946
49Storm E.E. et al. (2006) Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 133, 1831-1844
50Aoto K. et al. (2002) Mouse GLI3 regulates Fgf8 expression and apoptosis in the developing neural tube, face, and limb bud. Dev Biol 251, 320-332
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, 2439-2444
52Dale J.K. et al. (1997) Cooperation of BMP7 and SHH in the induction of forebrain ventral midline cells by prechordal mesoderm. Cell 90, 257-269
53Li H. et al. (1997) A single morphogenetic field gives rise to two retina primordia under the influence of the prechordal plate. Development 124, 603-615
54Pera E.M. and Kessel M. (1997) Patterning of the chick forebrain anlage by the prechordal plate. Development 124, 4153
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, 5533-5546
56Helms J.A., Cordero D. and Tapadia M.D. (2005) New insights into craniofacial morphogenesis. Development 132, 851-861
57Hu D. and Helms J.A. (1999) The role of Sonic hedgehog in normal and abnormal craniofacial morphogenesis. Development 126, 4873-4884
58Cordero D. et al. (2004) Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes. J Clin Invest 114, 485-494
59Cohen M.M. Jr. and Shiota K. (2002) Teratogenesis of holoprosencephaly. Am J Med Genet 109, 1-15
60Roessler E. and Muenke M. (1998) Holoprosencephaly: a paradigm for the complex genetics of brain development. J Inherit Metab Dis 21, 481-497
61Bendavid C. et al. (2006) Molecular evaluation of foetuses with holoprosencephaly shows high incidence of microdeletions in the HPE genes. Mun Genet 119, 1-8
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, 496-500
63El-Jaick K.B. et al. (2007) Functional analysis of mutations in TGIF associated with holoprosencephaly. Mol Genet Metab 90, 97-111
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, 17026-17031
65Schell-Apacik C. et al. (2003) SONIC HEDGEHOG mutations causing human holoprosencephaly impair neural patterning activity. Hum Genet 113, 170-177
66Traiffort E. et al. (2004) Functional characterization of sonic hedgehog mutations associated with holoprosencephaly. J Biol Chem 279, 42889-42897
67Cohen M.M. Jr. (1989) Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology 40, 211-235
68Barr M.J. et al. (1983) Holoprosencephaly in infants of diabetic mothers. J Pediatr 102, 565-568
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, 320-325
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, 10476-10481
71Li Y.X. et al. (2007) Fetal alcohol exposure impairs Hedgehog cholesterol modification and signaling. Lab Invest 87, 231-240
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, 4478-4484
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, 287-298
74Cooper M.K. et al. (2003) A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 33, 508-513
75Haas D. et al. (2007) Abnormal sterol metabolism in holoprosencephaly: studies in cultured lymphoblasts. J Med Genet 44, 298-305
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, 1244-1257
77Martinelli D.C. and Fan C.M. (2007) Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21, 1231-1243
78Seppala M. et al. (2007) Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest 117, 1575-1584
79Cole F. and Krauss R.S. (2003) Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon. Curr Biol 13, 411-415
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, 657-665
81Petryk A. et al. (2004) The mammalian twisted gastrulation gene functions in foregut and craniofacial development. Dev Biol 267, 374-386
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, 413-424
83Anderson R.M. et al. (2002) Chordin and noggin promote organizing centers of forebrain development in the mouse. Development 129, 4975-4987
84Bachiller D. et al. (2000) The organizer factors Chordin and Noggin are required for mouse forebrain development. Nature 403, 658-661
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, 1-17
86Bartholin L. et al. (2006) TGIF inhibits retinoid signaling. Mol Cell Biol 26, 990-1001
87Jin J.Z. et al. (2006) Expression and functional analysis of Tgif during mouse midline development. Dev Dyn 235, 547-553
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, 3639-3647
89Mar L. and Hoodless P.A. (2006) Embryonic fibroblasts from mice lacking Tgif were defective in cell cycling. Mol Cell Biol 26, 4302-4310
90Kuang C. et al. (2006) Intragenic deletion of Tgif causes defects in brain development. Hum Mol Genet 15, 3508-3519
91Ding J. et al. (1998) Cripto is required for correct orientation of the anterior-posterior axis in the mouse embryo. Nature 395, 702-707
92Marcucio R.S. et al. (2005) Molecular interactions coordinating the development of the forebrain and face. Dev Biol 284, 48-61
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, 24-31
94Ingham P.W. and Placzek M. (2006) Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 7, 841-850
95McMahon A.P., Ingham P.W. and Tabin C.J. (2003) Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol 53, 1-114
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, 647-656
97Okada A. et al. (2006) Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444, 369-373
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, 761-772
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, 1725-1735
100Hayhurst M. and McConnell S.K. (2003) Mouse models of holoprosencephaly. Curr Opin Neurol 16, 135-141
101Furuta Y., Piston D.W. and Hogan B.L. (1997) Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. Development 124, 2203-2212
102Cheng X. et al. (2006) Central roles of the roof plate in telencephalic development and holoprosencephaly. J Neurosci 26, 7640-7649
103Brown S.A. et al. (1998) Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired. Nat Genet 20, 180-183
104Nagai T. et al. (2000) Zic2 regulates the kinetics of neurulation. Proc Natl Acad Sci U S A 97, 1618-1623
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, 299-313
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, 1454-1468
107Chen L. et al. (2006) Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc Natl Acad Sci U S A 103, 16520-16525
108Varlet I. et al. (1997) Nodal signaling and axis formation in the mouse. Cold Spring Harb Symp Quant Biol 62, 105-113
109Jin O. et al. (2001) Otx2 and HNF3β genetically interact in anterior patterning. Int J Dev Biol 45, 357-365
110Andersson O. et al. (2006) Synergistic interaction between Gdf1 and Nodal during anterior axis development. Dev Biol 293, 370-381
Muenke M. and Beachy P.A. (2001) Holoprosencephaly. In The Metabolic & Molecular Bases of Inherited Disease (Scriver C. R. et al. ed.), pp. 62036230. McGraw-Hill, New York
Yamada S. et al. (2004) Phenotypic variability in human embryonic holoprosencephaly in the Kyoto Collection. Birth Defects Res Part A Clin Mol Teratol 70, 495508
Cohen M.M. Jr. (2006) Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res Part A Clin Mol Teratol 76, 658673
Dubourg C. et al. (2007) Holoprosencephaly. Orphanet J Rare Dis 2, 8
Ming J.E. and Muenke M. (2002) Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 71, 10171032
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Expert Reviews in Molecular Medicine
  • ISSN: -
  • EISSN: 1462-3994
  • URL: /core/journals/expert-reviews-in-molecular-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Metrics

Full text views

Total number of HTML views: 5
Total number of PDF views: 5 *
Loading metrics...

Abstract views

Total abstract views: 156 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 22nd October 2017. This data will be updated every 24 hours.