How to cite this WIREs title:
WIREs Dev Biol

Impact Factor: 3.883

Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans

Advanced Review

Anna Petryk, Daniel Graf, Ralph Marcucio

Published Online: Oct 22 2014

DOI: 10.1002/wdev.161

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

Holoprosencephaly (HPE) is the most common developmental defect of the forebrain characterized by inadequate or absent midline division of the forebrain into cerebral hemispheres, with concomitant midline facial defects in the majority of cases. Understanding the pathogenesis of HPE requires knowledge of the relationship between the developing brain and the facial structures during embryogenesis. A number of signaling pathways control and coordinate the development of the brain and face, including Sonic hedgehog, Bone morphogenetic protein, Fibroblast growth factor, and Nodal signaling. Mutations in these pathways have been identified in animal models of HPE and human patients. Because of incomplete penetrance and variable expressivity of HPE, patients carrying defined mutations may not manifest the disease at all, or have a spectrum of defects. It is currently unknown what drives manifestation of HPE in genetically at‐risk individuals, but it has been speculated that other gene mutations and environmental factors may combine as cumulative insults. HPE can be diagnosed in utero by a high‐resolution prenatal ultrasound or a fetal magnetic resonance imaging, sometimes in combination with molecular testing from chorionic villi or amniotic fluid sampling. Currently, there are no effective preventive methods for HPE. Better understanding of the mechanisms of gene–environment interactions in HPE would provide avenues for such interventions. WIREs Dev Biol 2015, 4:17–32. doi: 10.1002/wdev.161 This article is categorized under: Nervous System Development > Vertebrates: General Principles Birth Defects > Craniofacial and Nervous System Anomalies

Holoprosencephaly in humans and mice. (a) Normal human brain magnetic resonance imaging (MRI). The two cerebral hemispheres are completely separated. The septum (arrow) and the corpus callosum (arrowhead) are present. (Reprinted with permission from Ref . Copyright 2009 American Society for Clinical Investigation). (b) MRI of a neonate with alobar holoprosencephaly (HPE) showing a monoventricle (MV) and a large dorsal cyst (DC) posteriorly. (Reprinted with permission from Ref . Copyright 2010 John Wiley and Sons). (c) Transverse section of wild‐type mouse brain at birth. (d) Nonseparation of the brain and a large monoventricle in Twsg1^−/− mouse at birth (c and d: Reprinted with permission from Ref . Copyright 2004 Elsevier)

[ Normal View | Magnified View ]

Schematic representation of core pathways involved in forebrain development and holoprosencephaly (HPE). Classic HPE‐related pathways that signal predominantly at the ventral midline are shown in orange. The bone morphogenetic protein (BMP) pathway is shown in blue signals predominantly at the dorsal midline and is involved in midline interhemispheric (MIH) HPE. (Reprinted with permission from Ref . Copyright 2008 John Wiley and Sons)

[ Normal View | Magnified View ]

Nonlinearities in signaling may produce phenotypic variation. A model illustrating how nonlinear properties of a signaling pathway can produce phenotypic variation. By reducing SHH signaling a large amount of phenotypic variance could be produced owing to the nonlinear nature of the SHH pathway. (Reprinted with permission from Ref . Copyright 2009 Springer)

[ Normal View | Magnified View ]

Signaling centers instructing telencephalon. Frontolateral view of the telencephalon indicating its distinct signaling centers important for regional differentiation in relation to other developing head structures: the ventral center secreting SHH (red), the rostral center secreting FGF8 (blue), and the dorsal center secreting BMPs and Wnt (green). Cross‐regulation between the rostral, dorsal, and ventral signaling centers plays an essential role in patterning the early telencephalon. Cx, cortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; S, septum. (Reprinted with permission from Ref . Copyright 2009 Elsevier)

[ Normal View | Magnified View ]

Spatial relationships during development of the head. (a) A bright field image of a HH10 chicken embryo in ovo. Dorsal view showing regionalization of the neural tube into the prosencephalon (p), mesencephalon (ms), and metencephalon (mt). The anterior neural pore (anp) is located at the anterior end of the neural tube, and the neural tube is flanked by paraxial mesoderm (pm). (b) A sagittal section of a HH10 embryo that has been stained with bis‐benzimide and imaged using an epifluorescent microscope (Leica) showing the prosencephalon (p), mesencephalon (ms), the anterior neural pore (anp), the pharyngeal endoderm (pe), the facial ectoderm (fe), and the prechordal mesoderm (asterisk).

[ Normal View | Magnified View ]

Spectrum of craniofacial phenotypes in humans (a–e) and Twsg1^−/− mice (f–j). (a) Single central incisor; (b) microcephaly, midface hypoplasia with bilateral cleft lip and palate; (c) cyclopia with proboscis above the fused eye; and (d) hypotelorism and a single nostril. (a–d: Reprinted with permission from Ref . Copyright 2000 John Wiley and Sons). (e) Agnathia with downward displacement of the ears and microstomia. (Reprinted with permission from Ref . Copyright 2002 John Wiley and Sons). (f) Wild type; (g) severe anterior truncation; (h) cyclopia with proboscis; (i) single nostril with agnathia; and (j) agnathia. (f–j: Reprinted with permission from Ref . Copyright 2004 Elsevier)

[ Normal View | Magnified View ]

References

Geng, X, Oliver, G. Pathogenesis of holoprosencephaly. J Clin Invest 2009, 119:1403–1413.
Hahn, JS, Barnes, PD. Neuroimaging advances in holoprosencephaly: refining the spectrum of the midline malformation. Am J Med Genet C Semin Med Genet 2010, 154C:120–132.
Petryk, A, Anderson, RM, Jarcho, MP, Leaf, I, Carlson, CS, Klingensmith, J, Shawlot, W, O`Connor, MB. The mammalian twisted gastrulation gene functions in foregut and craniofacial development. Dev Biol 2004, 267:374–386.
Pauli, RM, Pettersen, JC, Arya, S, Gilbert, EF. Familial agnathia‐holoprosencephaly. Am J Med Genet 1983, 14:677–698.
Lipinski, RJ, Godin, EA, O`Leary‐Moore, SK, Parnell, SE, Sulik, KK. Genesis of teratogen‐induced holoprosencephaly in mice. Am J Med Genet C Semin Med Genet 2010, 154C:29–42.
Roessler, E, Muenke, M. The molecular genetics of holoprosencephaly. Am J Med Genet C Semin Med Genet 2010, 154C:52–61.
Orioli, IM, Castilla, EE. Epidemiology of holoprosencephaly: prevalence and risk factors. Am J Med Genet C Semin Med Genet 2010, 154C:13–21.
Roessler, E, Belloni, E, Gaudenz, K, Jay, P, Berta, P, Scherer, SW, Tsui, LC, Muenke, M. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 1996, 14:357–360.
Cohen, MM Jr, Shiota, K. Teratogenesis of holoprosencephaly. Am J Med Genet 2002, 109:1–15.
Muenke, M, Beachy, PA. Genetics of ventral forebrain development and holoprosencephaly. Curr Opin Genet Dev 2000, 10:262–269.
Bendavid, C, Rochard, L, Dubourg, C, Seguin, J, Gicquel, I, Pasquier, L, Vigneron, J, Laquerriere, A, Marcorelles, P, Jeanne‐Pasquier, C, et al. Array‐CGH analysis indicates a high prevalence of genomic rearrangements in holoprosencephaly: an updated map of candidate loci. Hum Mutat 2009, 30:1175–1182.
Shiota, K, Yamada, S. Early pathogenesis of holoprosencephaly. Am J Med Genet C Semin Med Genet 2010, 154C:22–28.
Ming, JE, Muenke, M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 2002, 71:1017–1032.
Gongal, PA, French, CR, Waskiewicz, AJ. Aberrant forebrain signaling during early development underlies the generation of holoprosencephaly and coloboma. Biochim Biophys Acta 1812, 2011:390–401.
Schachter, KA, Krauss, RS. Murine models of holoprosencephaly. Curr Top Dev Biol 2008, 84:139–170.
Hu, D, Marcucio, RS. A SHH‐responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm. Development 2009, 136:107–116.
Hu, D, Marcucio, R, Helms, JA. A zone of frontonasal ectoderm regulates patterning and growth in the face. Development 2003, 130:1749–1758.
Sulik, KK, Dehart, DB, Rogers, JM, Chernoff, N. Teratogenicity of low doses of all‐trans retinoic acid in presomite mouse embryos. Teratology 1995, 51:398–403.
Helms, JA, Kim, CH, Hu, D, Minkoff, R, Thaller, C, Eichele, G. Sonic hedgehog participates in craniofacial morphogenesis and is down‐regulated by teratogenic doses of retinoic acid. Dev Biol 1997, 187:25–35.
Ahlgren, SC, Thakur, V, Bronner‐Fraser, M. Sonic hedgehog rescues cranial neural crest from cell death induced by ethanol exposure. Proc Natl Acad Sci USA 2002, 99:10476–10481.
Cohen, MM Jr. Perspectives on holoprosencephaly: Part I. Epidemiology, genetics, and syndromology. Teratology 1989, 40:211–235.
Hahn, JS, Barnes, PD, Clegg, NJ, Stashinko, EE. Septopreoptic holoprosencephaly: a mild subtype associated with midline craniofacial anomalies. AJNR Am J Neuroradiol 2010, 31:1596–1601.
Marcorelles, P, Laquerriere, A. Neuropathology of holoprosencephaly. Am J Med Genet C Semin Med Genet 2010, 154C:109–119.
Fertuzinhos, S, Krsnik, Z, Kawasawa, YI, Rasin, MR, Kwan, KY, Chen, JG, Judas, M, Hayashi, M, Sestan, N. Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cereb Cortex 2009, 19:2196–2207.
Weaver, DD, Solomon, BD, Akin‐Samson, K, Kelley, RI, Muenke, M. Cyclopia (synophthalmia) in Smith‐Lemli‐Opitz syndrome: first reported case and consideration of mechanism. Am J Med Genet C Semin Med Genet 2010, 154C:142–145.
Muenke, M, Cohen, MM Jr. Genetic approaches to understanding brain development: holoprosencephaly as a model. Ment Retard Dev Disabil Res Rev 2000, 6:15–21.
Schiffer, C, Tariverdian, G, Schiesser, M, Thomas, MC, Sergi, C. Agnathia‐otocephaly complex: report of three cases with involvement of two different Carnegie stages. Am J Med Genet 2002, 112:203–208.
Cohen, MM Jr, Sulik, KK. Perspectives on holoprosencephaly: Part II. Central nervous system, craniofacial anatomy, syndrome commentary, diagnostic approach, and experimental studies. J Craniofac Genet Dev Biol 1992, 12:196–244.
Kauvar, EF, Solomon, BD, Curry, CJ, van Essen, AJ, Janssen, N, Dutra, A, Roessler, E, Muenke, M. Holoprosencephaly and agnathia spectrum: presentation of two new patients and review of the literature. Am J Med Genet C Semin Med Genet 2010, 154C:158–169.
Kauvar, EF, Muenke, M. Holoprosencephaly: recommendations for diagnosis and management. Curr Opin Pediatr 2010, 22:687–695.
Demyer, W, Zeman, W, Palmer, CG. The face predicts the brain: diagnostic significance of median facial anomalies for holoprosencephaly (arhinencephaly). Pediatrics 1964, 34:256–263.
Anderson, RM, Lawrence, AR, Stottmann, RW, Bachiller, D, Klingensmith, J. Chordin and noggin promote organizing centers of forebrain development in the mouse. Development 2002, 129:4975–4987.
Chiang, C, Litingtung, Y, Lee, E, Young, KE, Corden, JL, Westphal, H, Beachy, PA. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996, 383:407–413.
Cordero, D, Marcucio, R, Hu, D, Gaffield, W, Tapadia, M, Helms, JA. Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes. J Clin Invest 2004, 114:485–494.
Chen, JK, Taipale, J, Cooper, MK, Beachy, PA. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 2002, 16:2743–2748.
Dipple, KM, McCabe, ER. Phenotypes of patients with "simple" Mendelian disorders are complex traits: thresholds, modifiers, and systems dynamics. Am J Hum Genet 2000, 66:1729–1735.
Nanni, L, Ming, JE, Bocian, M, Steinhaus, K, Bianchi, DW, Die‐Smulders, C, Giannotti, A, Imaizumi, K, Jones, KL, Campo, MD, et al. The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly. Hum Mol Genet 1999, 8:2479–2488.
Vockley, J, Rinaldo, P, Bennett, MJ, Matern, D, Vladutiu, GD. Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways. Mol Genet Metab 2000, 71:10–18.
Nadeau, JH. Modifier genes in mice and humans. Nat Rev Genet 2001, 2:165–174.
Feinberg, AP, Irizarry, RA. Evolution in health and medicine Sackler colloquium: stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc Natl Acad Sci USA 2010, 107(suppl 1):1757–1764.
Solomon, BD, Rosenbaum, KN, Meck, JM, Muenke, M. Holoprosencephaly due to numeric chromosome abnormalities. Am J Med Genet C Semin Med Genet 2010, 154C:146–148.
Croen, LA, Shaw, GM, Lammer, EJ. Holoprosencephaly: epidemiologic and clinical characteristics of a California population. Am J Med Genet 1996, 64:465–472.
Dubourg, C, Lazaro, L, Pasquier, L, Bendavid, C, Blayau, M, Le Duff, F, Durou, MR, Odent, S, David, V. Molecular screening of SHH, ZIC2, SIX3, and TGIF genes in patients with features of holoprosencephaly spectrum: mutation review and genotype‐phenotype correlations. Hum Mutat 2004, 24:43–51.
Olsen, CL, Hughes, JP, Youngblood, LG, Sharpe‐Stimac, M. Epidemiology of holoprosencephaly and phenotypic characteristics of affected children: New York State, 1984‐1989. Am J Med Genet 1997, 73:217–226.
Croen, LA, Shaw, GM, Lammer, EJ. Risk factors for cytogenetically normal holoprosencephaly in California: a population‐based case‐control study. Am J Med Genet 2000, 90:320–325.
Aoto, K, Shikata, Y, Higashiyama, D, Shiota, K, Motoyama, J. 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 2008, 82:224–231.
Johnson, CY, Rasmussen, SA. Non‐genetic risk factors for holoprosencephaly. Am J Med Genet C Semin Med Genet 2010, 154C:73–85.
Correa, A, Gilboa, SM, Besser, LM, Botto, LD, Moore, CA, Hobbs, CA, Cleves, MA, Riehle‐Colarusso, TJ, Waller, DK, Reece, EA. Diabetes mellitus and birth defects. Am J Obstet Gynecol 2008, 199:237.e1–237.e9.
Barr, M Jr, Hanson, JW, Currey, K, Sharp, S, Toriello, H, Schmickel, RD, Wilson, GN. Holoprosencephaly in infants of diabetic mothers. J Pediatr 1983, 102:565–568.
Higashiyama, D, Saitsu, H, Komada, M, Takigawa, T, Ishibashi, M, Shiota, K. Sequential developmental changes in holoprosencephalic mouse embryos exposed to ethanol during the gastrulation period. Birth Defects Res A Clin Mol Teratol 2007, 79:513–523.
Kietzman, HW, Everson, JL, Sulik, KK, Lipinski, RJ. The teratogenic effects of prenatal ethanol exposure are exacerbated by Sonic Hedgehog or GLI2 haploinsufficiency in the mouse. PLoS One 2014, 9:e89448.
Ronen, GM, Andrews, WL. Holoprosencephaly as a possible embryonic alcohol effect. Am J Med Genet 1991, 40:151–154.
Bonnemann, C, Meinecke, P. Holoprosencephaly as a possible embryonic alcohol effect: another observation. Am J Med Genet 1990, 37:431–432.
Lammer, EJ, Chen, DT, Hoar, RM, Agnish, ND, Benke, PJ, Braun, JT, Curry, CJ, Fernhoff, PM, Grix, AW Jr, Lott, IT, et al. Retinoic acid embryopathy. N Engl J Med 1985, 313:837–841.
Porter, JA, Young, KE, Beachy, PA. Cholesterol modification of hedgehog signaling proteins in animal development. Science 1996, 274:255–259.
Lanoue, L, Dehart, DB, Hinsdale, ME, Maeda, N, Tint, GS, Sulik, KK. 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 1997, 73:24–31.
Edison, RJ, Muenke, M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004, 131:287–298.
Miller, EA, Rasmussen, SA, Siega‐Riz, AM, Frias, JL, Honein, MA. Risk factors for non‐syndromic holoprosencephaly in the National Birth Defects Prevention Study. Am J Med Genet C Semin Med Genet 2010, 154C:62–72.
Bartholin, L, Powers, SE, Melhuish, TA, Lasse, S, Weinstein, M, Wotton, D. TGIF inhibits retinoid signaling. Mol Cell Biol 2006, 26:990–1001.
Kousseff, BG. Gestational diabetes mellitus (class A): a human teratogen? Am J Med Genet 1999, 83:402–408.
Sulik, KK, Cook, CS, Webster, WS. Teratogens and craniofacial malformations: relationships to cell death. Development 1988, 103(suppl):213–231.
Ornoy, A. Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy. Reprod Toxicol 2007, 24:31–41.
Davis, WL, Crawford, LA, Cooper, OJ, Farmer, GR, Thomas, D, Freeman, BL. Generation of radical oxygen species by neural crest cells treated in vitro with isotretinoin and 4‐oxo‐isotretinoin. J Craniofac Genet Dev Biol 1990, 10:295–310.
Kay, HH, Grindle, KM, Magness, RR. Ethanol exposure induces oxidative stress and impairs nitric oxide availability in the human placental villi: a possible mechanism of toxicity. Am J Obstet Gynecol 2000, 182:682–688.
Hamburger, V, Hamilton, HL. A series of normal stages in the development of the chick embryo. J Morphol 1951, 88:49–92.
Groves, AK, LaBonne, C. Setting appropriate boundaries: fate, patterning and competence at the neural plate border. Dev Biol 2014, 389:2–12.
Colas, JF, Schoenwolf, GC. Towards a cellular and molecular understanding of neurulation. Dev Dyn 2001, 221:117–145.
Evans, DJ, Noden, DM. Spatial relations between avian craniofacial neural crest and paraxial mesoderm cells. Dev Dyn 2006, 235:1310–1325.
Noden, DM, Marcucio, R, Borycki, AG, Emerson, CP Jr. Differentiation of avian craniofacial muscles: I. Patterns of early regulatory gene expression and myosin heavy chain synthesis. Dev Dyn 1999, 216:96–112.
Noden, DM, Trainor, PA. Relations and interactions between cranial mesoderm and neural crest populations. J Anat 2005, 207:575–601.
Murdoch, JN, Copp, AJ. The relationship between sonic Hedgehog signaling, cilia, and neural tube defects. Birth Defects Res A Clin Mol Teratol 2010, 88:633–652.
Le Dreau, G, Marti, E. Dorsal‐ventral patterning of the neural tube: a tale of three signals. Dev Neurobiol 2012, 72:1471–1481.
Muller, F, Albert, S, Blader, P, Fischer, N, Hallonet, M, Strahle, U. Direct action of the nodal‐related signal cyclops in induction of sonic hedgehog in the ventral midline of the CNS. Development 2000, 127:3889–3897.
Rubenstein, JL, Shimamura, K, Martinez, S, Puelles, L. Regionalization of the prosencephalic neural plate. Annu Rev Neurosci 1998, 21:445–477.
Storm, EE, Garel, S, Borello, U, Hebert, JM, Martinez, S, McConnell, SK, Martin, GR, Rubenstein, JL. Dose‐dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 2006, 133:1831–1844.
Ohkubo, Y, Chiang, C, Rubenstein, JL. Coordinate regulation and synergistic actions of BMP4, SHH and FGF8 in the rostral prosencephalon regulate morphogenesis of the telencephalic and optic vesicles. Neuroscience 2002, 111:1–17.
Hoch, RV, Rubenstein, JL, Pleasure, S. Genes and signaling events that establish regional patterning of the mammalian forebrain. Semin Cell Dev Biol 2009, 20:378–386.
Macdonald, R, Barth, KA, Xu, Q, Holder, N, Mikkola, I, Wilson, SW. Midline signalling is required for Pax gene regulation and patterning of the eyes. Development 1995, 121:3267–3278.
Diewert, VM, Lozanoff, S. A morphometric analysis of human embryonic craniofacial growth in the median plane during primary palate formation. J Craniofac Genet Dev Biol 1993, 13:147–161.
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, 213:646–662.
Marcucio, RS, Young, NM, Hu, D, Hallgrimsson, B. Mechanisms that underlie co‐variation of the brain and face. Genesis 2011, 49:177–189.
Marcucio, RS, Cordero, DR, Hu, D, Helms, JA. Molecular interactions coordinating the development of the forebrain and face. Dev Biol 2005, 284:48–61.
Young, NM, Chong, HJ, Hu, D, Hallgrimsson, B, Marcucio, RS. Quantitative analyses link modulation of sonic hedgehog signaling to continuous variation in facial growth and shape. Development 2010, 137:3405–3409.
Muenke, M, Beachy, PA. Holoprosencephaly. In: Scriver, CR, Beaudet, AL, Sly, WS, Valle, D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw‐Hill; 2001, 6203–6230.
Balk, K, Biesecker, LG. The clinical atlas of Greig cephalopolysyndactyly syndrome. Am J Med Genet A 2008, 146A:548–557.
Hallgrimsson, B, Jamniczky, H, Young, NM, Rolian, C, Parsons, TE, Boughner, JC, Marcucio, RS. Deciphering the palimpsest: studying the relationship between morphological integration and phenotypic covariation. Evol Biol 2009, 36:355–376.
Hu, D, Marcucio, RS. Unique organization of the frontonasal ectodermal zone in birds and mammals. Dev Biol 2009, 325:200–210.
Young, NM, Hu, D, Lainoff, AJ, Smith, FJ, Diaz, R, Tucker, AS, Trainor, PA, Schneider, RA, Hallgrimsson, B, Marcucio, RS. Embryonic bauplans and the developmental origins of facial diversity and constraint. Development 2014, 141:1059–1063.
Ashique, AM, Fu, K, Richman, JM. Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion. Development 2002, 129:4647–4660.
Foppiano, S, Hu, D, Marcucio, RS. Signaling by bone morphogenetic proteins directs formation of an ectodermal signaling center that regulates craniofacial development. Dev Biol 2007, 312:103–114.
Geetha‐Loganathan, P, Nimmagadda, S, Antoni, L, Fu, K, Whiting, CJ, Francis‐West, P, Richman, JM. Expression of WNT signalling pathway genes during chicken craniofacial development. Dev Dyn 2009, 238:1150–1165.
Abzhanov, A, Protas, M, Grant, BR, Grant, PR, Tabin, CJ. Bmp4 and morphological variation of beaks in Darwin`s finches. Science 2004, 305:1462–1465.
Sampath, K, Rubinstein, AL, Cheng, AM, Liang, JO, Fekany, K, Solnica‐Krezel, L, Korzh, V, Halpern, ME, Wright, CV. Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature 1998, 395:185–189.
Lowe, LA, Yamada, S, Kuehn, MR. Genetic dissection of nodal function in patterning the mouse embryo. Development 2001, 128:1831–1843.
Fernandes, M, Hebert, JM. The ups and downs of holoprosencephaly: dorsal versus ventral patterning forces. Clin Genet 2008, 73:413–423.
Shen, MM. Nodal signaling: developmental roles and regulation. Development 2007, 134:1023–1034.
Heyer, J, Escalante‐Alcalde, D, Lia, M, Boettinger, E, Edelmann, W, Stewart, CL, Kucherlapati, R. Postgastrulation Smad2‐deficient embryos show defects in embryo turning and anterior morphogenesis. Proc Natl Acad Sci USA 1999, 96:12595–12600.
Hoodless, PA, Pye, M, Chazaud, C, Labbe, E, Attisano, L, Rossant, J, Wrana, JL. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev 2001, 15:1257–1271.
Nomura, M, Li, E. Smad2 role in mesoderm formation, left‐right patterning and craniofacial development. Nature 1998, 393:786–790.
Song, J, Oh, SP, Schrewe, H, Nomura, M, Lei, H, Okano, M, Gridley, T, Li, E. The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice. Dev Biol 1999, 213:157–169.
Chu, J, Ding, J, Jeays‐Ward, K, Price, SM, Placzek, M, Shen, MM. Non‐cell‐autonomous role for Cripto in axial midline formation during vertebrate embryogenesis. Development 2005, 132:5539–5551.
Andersson, O, Reissmann, E, Jornvall, H, Ibanez, CF. Synergistic interaction between Gdf1 and Nodal during anterior axis development. Dev Biol 2006, 293:370–381.
Cohen, MM Jr. Holoprosencephaly: clinical, anatomic, and molecular dimensions. Birth Defects Res A Clin Mol Teratol 2006, 76:658–673.
Cooper, MK, Wassif, CA, Krakowiak, PA, Taipale, J, Gong, R, Kelley, RI, Porter, FD, Beachy, PA. A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis. Nat Genet 2003, 33:508–513.
Buglino, JA, Resh, MD. Hhat is a palmitoylacyltransferase with specificity for N‐palmitoylation of Sonic Hedgehog. J Biol Chem 2008, 283:22076–22088.
Wassif, CA, Maslen, C, Kachilele‐Linjewile, S, Lin, D, Linck, LM, Connor, WE, Steiner, RD, Porter, FD. Mutations in the human sterol Δ7‐reductase gene at 11q12‐13 cause Smith‐Lemli‐Opitz syndrome. Am J Hum Genet 1998, 63:55–62.
Dennis, JF, Kurosaka, H, Iulianella, A, Pace, J, Thomas, N, Beckham, S, Williams, T, Trainor, PA. Mutations in Hedgehog acyltransferase (Hhat) perturb Hedgehog signaling, resulting in severe acrania‐holoprosencephaly‐agnathia craniofacial defects. PLoS Genet 2012, 8:e1002927.
Kawakami, T, Kawcak, T, Li, YJ, Zhang, W, Hu, Y, Chuang, PT. Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 2002, 129:5753–5765.
Ma, Y, Erkner, A, Gong, R, Yao, S, Taipale, J, Basler, K, Beachy, PA. Hedgehog‐mediated patterning of the mammalian embryo requires transporter‐like function of dispatched. Cell 2002, 111:63–75.
Zhang, XM, Ramalho‐Santos, M, McMahon, AP. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R symmetry by the mouse node. Cell 2001, 106:781–792.
Goodrich, LV, Milenkovic, L, Higgins, KM, Scott, MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 1997, 277:1109–1113.
Jenkins, D. Hedgehog signalling: emerging evidence for non‐canonical pathways. Cell Signal 2009, 21:1023–1034.
Ding, Q, Motoyama, J, Gasca, S, Mo, R, Sasaki, H, Rossant, J, Hui, CC. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 1998, 125:2533–2543.
Matise, MP, Epstein, DJ, Park, HL, Platt, KA, Joyner, AL. Gli2 is required for induction of floor plate and adjacent cells, but not most ventral neurons in the mouse central nervous system. Development 1998, 125:2759–2770.
Roessler, E, Du, YZ, Mullor, JL, Casas, E, Allen, WP, Gillessen‐Kaesbach, G, Roeder, ER, Ming, JE, Ruiz i Altaba, A, Muenke, M. Loss‐of‐function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly‐like features. Proc Natl Acad Sci USA 2003, 100:13424–13429.
Grove, EA, Tole, S, Limon, J, Yip, L, Ragsdale, CW. The hem of the embryonic cerebral cortex is defined by the expression of multiple Wnt genes and is compromised in Gli3‐deficient mice. Development 1998, 125:2315–2325.
Taniguchi, K, Anderson, AE, Sutherland, AE, Wotton, D. Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway. PLoS Genet 2012, 8:e1002524.
Kang, JS, Zhang, W, Krauss, RS. Hedgehog signaling: cooking with Gas1. Sci STKE 2007, 2007:pe50.
Allen, BL, Tenzen, T, McMahon, AP. The Hedgehog‐binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev 2007, 21:1244–1257.
Cole, F, Krauss, RS. Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon. Curr Biol 2003, 13:411–415.
Zhang, W, Hong, M, Bae, GU, Kang, JS, Krauss, RS. Boc modifies the holoprosencephaly spectrum of Cdo mutant mice. Dis Model Mech 2011, 4:368–380.
Seppala, M, Depew, MJ, Martinelli, DC, Fan, CM, Sharpe, PT, Cobourne, MT. Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest 2007, 117:1575–1584.
Huang, X, Litingtung, Y, Chiang, C. Ectopic sonic hedgehog signaling impairs telencephalic dorsal midline development: implication for human holoprosencephaly. Hum Mol Genet 2007, 16:1454–1468.
Bertolino, E, Reimund, B, Wildt‐Perinic, D, Clerc, RG. A novel homeobox protein which recognizes a TGT core and functionally interferes with a retinoid‐responsive motif. J Biol Chem 1995, 270:31178–31188.
Gongal, PA, Waskiewicz, AJ. Zebrafish model of holoprosencephaly demonstrates a key role for TGIF in regulating retinoic acid metabolism. Hum Mol Genet 2008, 17:525–538.
Thisse, B, Thisse, C. Functions and regulations of fibroblast growth factor signaling during embryonic development. Dev Biol 2005, 287:390–402.
Hayhurst, M, Gore, BB, Tessier‐Lavigne, M, McConnell, SK. Ongoing sonic hedgehog signaling is required for dorsal midline formation in the developing forebrain. Dev Neurobiol 2008, 68:83–100.
Roessler, E, Lacbawan, F, Dubourg, C, Paulussen, A, Herbergs, J, Hehr, U, Bendavid, C, Zhou, N, Ouspenskaia, M, Bale, S, et al. The full spectrum of holoprosencephaly‐associated mutations within the ZIC2 gene in humans predicts loss‐of‐function as the predominant disease mechanism. Hum Mutat 2009, 30:E541–E554.
Arauz, RF, Solomon, BD, Pineda‐Alvarez, DE, Gropman, AL, Parsons, JA, Roessler, E, Muenke, M. A hypomorphic allele in the FGF8 gene contributes to holoprosencephaly and is allelic to gonadotropin‐releasing hormone deficiency in humans. Mol Syndromol 2010, 1:59–66.
Nohe, A, Keating, E, Knaus, P, Petersen, NO. Signal transduction of bone morphogenetic protein receptors. Cell Signal 2004, 16:291–299.
Fuentealba, LC, Eivers, E, Ikeda, A, Hurtado, C, Kuroda, H, Pera, EM, De Robertis, EM. Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal. Cell 2007, 131:980–993.
Gazzerro, E, Canalis, E. Bone morphogenetic proteins and their antagonists. Rev Endocr Metab Disord 2006, 7:51–65.
Ross, JJ, Shimmi, O, Vilmos, P, Petryk, A, Kim, H, Gaudenz, K, Hermanson, S, Ekker, SC, O`Connor, MB, Marsh, JL. Twisted gastrulation is a conserved extracellular BMP antagonist. Nature 2001, 410:479–483.
Fernandes, M, Gutin, G, Alcorn, H, McConnell, SK, Hebert, JM. Mutations in the BMP pathway in mice support the existence of two molecular classes of holoprosencephaly. Development 2007, 134:3789–3794.
Bachiller, D, Klingensmith, J, Kemp, C, Belo, JA, Anderson, RM, May, SR, McMahon, JA, McMahon, AP, Harland, RM, Rossant, J, et al. The organizer factors Chordin and Noggin are required for mouse forebrain development. Nature 2000, 403:658–661.
Lana‐Elola, E, Tylzanowski, P, Takatalo, M, Alakurtti, K, Veistinen, L, Mitsiadis, TA, Graf, D, Rice, R, Luyten, FP, Rice, DP. Noggin allele mice exhibit a microform of holoprosencephaly. Hum Mol Genet 2011, 20:4005–4015.
Oelgeschlager, M, Larrain, J, Geissert, D, De Robertis, EM. The evolutionarily conserved BMP‐binding protein Twisted gastrulation promotes BMP signalling. Nature 2000, 405:757–763.
Zakin, L, De Robertis, EM. Inactivation of mouse Twisted gastrulation reveals its role in promoting Bmp4 activity during forebrain development. Development 2004, 131:413–424.
Graf, D, Timmons, PM, Hitchins, M, Episkopou, V, Moore, G, Ito, T, Fujiyama, A, Fisher, AG, Merkenschlager, M. Evolutionary conservation, developmental expression, and genomic mapping of mammalian Twisted gastrulation. Mamm Genome 2001, 12:554–560.
Kauvar, EF, Hu, P, Pineda‐Alvarez, DE, Solomon, BD, Dutra, A, Pak, E, Blessing, B, Proud, V, Shanske, AL, Stevens, CA, et al. Minimal evidence for a direct involvement of twisted gastrulation homolog 1 (TWSG1) gene in human holoprosencephaly. Mol Genet Metab 2011, 102:470–480.
Wenghoefer, M, Ettema, AM, Sina, F, Geipel, A, Kuijpers‐Jagtman, AM, Hansmann, H, Borstlap, WA, Berge, S. Prenatal ultrasound diagnosis in 51 cases of holoprosencephaly: craniofacial anatomy, associated malformations, and genetics. Cleft Palate Craniofac J 2010, 47:15–21.
Mercier, S, Dubourg, C, Belleguic, M, Pasquier, L, Loget, P, Lucas, J, Bendavid, C, Odent, S. Genetic counseling and "molecular" prenatal diagnosis of holoprosencephaly (HPE). Am J Med Genet C Semin Med Genet 2010, 154C:191–196.
Pineda‐Alvarez, DE, Dubourg, C, David, V, Roessler, E, Muenke, M. Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients. Am J Med Genet C Semin Med Genet 2010, 154C:93–101.
Curry, CJ, Carey, JC, Holland, JS, Chopra, D, Fineman, R, Golabi, M, Sherman, S, Pagon, RA, Allanson, J, Shulman, S, et al. Smith‐Lemli‐Opitz syndrome‐type II: multiple congenital anomalies with male pseudohermaphroditism and frequent early lethality. Am J Med Genet 1987, 26:45–57.
Levey, EB, Stashinko, E, Clegg, NJ, Delgado, MR. Management of children with holoprosencephaly. Am J Med Genet C Semin Med Genet 2010, 154C:183–190.
Solomon, BD, Mercier, S, Velez, JI, Pineda‐Alvarez, DE, Wyllie, A, Zhou, N, Dubourg, C, David, V, Odent, S, Roessler, E, et al. Analysis of genotype‐phenotype correlations in human holoprosencephaly. Am J Med Genet C Semin Med Genet 2010, 154C:133–141.
Czeizel, AE, Dudas, I. Prevention of the first occurrence of neural‐tube defects by periconceptional vitamin supplementation. N Engl J Med 1992, 327:1832–1835.
Billington, CJ Jr, Schmidt, B, Zhang, L, Hodges, JS, Georgieff, MK, Schotta, G, Gopalakrishnan, R, Petryk, A. Maternal diet supplementation with methyl donors and increased parity affect the incidence of craniofacial defects in the offspring of twisted gastrulation mutant mice. J Nutr 2013, 143:332–339.

Society Partners

	Free online access to WIREs Developmental Biology is a member benefit. Learn More
	SDB Collaborative Resources
	Society for Developmental Biology Homepage

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts