Neural tube defects (NTD) occur when the flat neural plate epithelium fails to fold into the neural tube, the precursor to the brain and spinal cord. Squint (Sqt/Ndr1), a Nodal ligand, and One-eyed pinhead (Oep), a component of the Nodal receptor, are required for anterior neural tube closure in zebrafish. The NTD in sqt and Zoep mutants are incompletely penetrant. The penetrance of several defects in sqt mutants increases upon heat or cold shock. In this project, undergraduate students tested whether temperature influences the Zoep open neural tube phenotype. Single pairs of adults were spawned at 28.5°C, the normal temperature for zebrafish, and one half of the resulting embryos were moved to 34°C at different developmental time points. Analysis of variance indicated temperature and clutch/genetic background significantly contributed to the penetrance of the open neural tube phenotype. Heat shock affected the embryos only at or before the midblastula stage. Many factors, including temperature changes in the mother, nutrition, and genetic background, contribute to NTD in humans. Thus, sqt and Zoep mutants may serve as valuable models for studying the interactions between genetics and the environment during neurulation.
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References
1.
ParkerSE, MaiCT, CanfieldMA, RickardR, WangY, MeyerRE, et al.Updated National Birth Prevalence estimates for selected birth defects in the United States, 2004–2006. Birth Defects Res A Clin Mol Teratol, 2010; 88:1008–1016.
CoppAJ, GreeneNDE, MurdochJN. The genetic basis of mammalian neurulation. Nat Rev Genet, 2003; 4:784–793.
4.
AuKS, Ashley-KochA, NorthrupH. Epidemiologic and genetic aspects of spina bifida and other neural tube defects. Dev Disabil Res Rev, 2010; 16:6–15.
5.
DreierJW, AndersenAM, Berg-BeckhoffG. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics, 2014; 133:e674–e688.
6.
MorettiME, Bar-OzB, FriedS, KorenG. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology, 2005; 16:216–219.
7.
ZohnIE. Mouse as a model for multifactorial inheritance of neural tube defects. Birth Defects Res C Embryo Today, 2012; 96:193–205.
8.
KappenC. Modeling anterior development in mice: diet as modulator of risk for neural tube defects. Am J Med Genet C Semin Med Genet, 2013; 163C:333–356.
9.
ImbardA, BenoistJF, BlomHJ. Neural tube defects, folic acid and methylation. Int J Environ Res Public Health, 2013; 10:4352–4389.
10.
CarmichaelSL, RasmussenSA, ShawGM. Prepregnancy obesity: a complex risk factor for selected birth defects. Birth Defects Res A Clin Mol Teratol, 2010; 88:804–810.
11.
LoweryLA, SiveH. Strategies of vertebrate neurulation and a re-evaluation of teleost neural tube formation. Mech Dev, 2004; 121:1189–1197.
12.
KimmelCB, BallardWW, KimmelSR, UllmannB, SchillingTF. Stages of embryonic development of the zebrafish. Dev Dyn, 1995; 203:253–310.
13.
PapanC, Campos-OrtegaJA. On the formation of the neural keel and neural tube in zebrafish. Rouxs Arch Dev Biol, 1994; 203:178–186.
14.
GreeneND, StanierP, CoppAJ. Genetics of human neural tube defects. Hum Mol Genet, 2009; 18:R113–R129.
HarrisMJ, JuriloffDM. An update to the list of mouse mutants with neural tube closure defects and advances toward a complete genetic perspective of neural tube closure. Birth Defects Res A Clin Mol Teratol, 2010; 88:653–669.
17.
HarrisMJ, JuriloffDM. Mouse mutants with neural tube closure defects and their role in understanding human neural tube defects. Birth Defects Res A Clin Mol Teratol, 2007; 79:187–210.
18.
WallingfordJB, HarlandRM. Neural tube closure requires Dishevelled-dependent convergent extension of the midline. Development, 2002; 129:5815–5825.
19.
CirunaB, JennyA, LeeD, MlodzikM, SchierAF. Planar cell polarity signalling couples cell division and morphogenesis during neurulation. Nature, 2006; 439:220–224.
20.
CaiC, ShiO. Genetic evidence in planar cell polarity signaling pathway in human neural tube defects. Front Med, 2014; 8:68–78.
21.
LeleZ, FolchertA, ConchaM, RauchGJ, GeislerR, RosaF, et al.Parachute/n-cadherin is required for morphogenesis and maintained integrity of the zebrafish neural tube. Development, 2002; 129:3281–3294.
22.
HongE, BrewsterR. N-cadherin is required for the polarized cell behaviors that drive neurulation in the zebrafish. Development, 2006; 133:3895–3905.
23.
Aquilina-BeckA, IlaganK, LiuQ, LiangJO. Nodal signaling is required for closure of the anterior neural tube in zebrafish. BMC Dev Biol, 2007; 7:126.
24.
RadiceGL, RayburnH, MatsunamiH, KnudsenKA, TakeichiM, HynesRO. Developmental defects in mouse embryos lacking N-cadherin. Dev Biol, 1997; 181:64–78.
25.
HalpernME, LiangJO, GamseJT. Leaning to the left: laterality in the zebrafish forebrain. Trends Neurosci, 2003; 26:308–313.
26.
SchierAF, TalbotWS. Nodal signaling and the zebrafish organizer. Int J Dev Biol, 2001; 45:289–297.
27.
SchierAF, ShenMM. Nodal signalling in vertebrate development. Nature, 2000; 403:385–389.
28.
LiangJO, RubinsteinAL. Patterning of the zebrafish embryo by nodal signals. Curr Top Dev Biol, 2003; 55:143–171.
29.
FeldmanB, DouganST, SchierAF, TalbotWS. Nodal-related signals establish mesendodermal fate and trunk neural identity in zebrafish. Curr Biol, 2000; 10:531–534.
30.
SirotkinHI, DouganST, SchierAF, TalbotWS. Bozozok and squint act in parallel to specify dorsal mesoderm and anterior neuroectoderm in zebrafish. Development, 2000; 127:2583–2592.
31.
GoreAV, MaegawaS, CheongA, GilliganPC, WeinbergES, SampathK. The zebrafish dorsal axis is apparent at the four-cell stage. Nature, 2005; 438:1030–1035.
32.
FeldmanB, GatesMA, EganES, DouganST, RennebeckG, SirotkinHI, et al.Zebrafish organizer development and germ-layer formation require nodal-related signals. Nature, 1998; 395:181–185.
33.
GritsmanK, ZhangJ, ChengS, HeckscherE, TalbotWS, SchierAF. The EGF-CFC protein one-eyed pinhead is essential for nodal signaling. Cell, 1999; 97:121–132.
34.
SchierAF, NeuhaussSC, HarveyM, MalickiJ, Solnica-KrezelL, StainierDY, et al.Mutations affecting the development of the embryonic zebrafish brain. Development, 1996; 123:165–178.
35.
DouganST, WargaRM, KaneDA, SchierAF, TalbotWS. The role of the zebrafish nodal-related genes squint and cyclops in patterning of mesendoderm. Development, 2003; 130:1837–1851.
36.
HattaK, KimmelCB, HoRK, WalkerC. The cyclops mutation blocks specification of the floor plate of the zebrafish central nervous system. Nature, 1991; 350:339–341.
37.
SchierAF, NeuhaussSC, HeldeKA, TalbotWS, DrieverW. The one-eyed pinhead gene functions in mesoderm and endoderm formation in zebrafish and interacts with no tail. Development, 1997; 124:327–342.
38.
SampathK, RubinsteinAL, ChengAM, LiangJO, FekanyK, Solnica-KrezelL, et al.Induction of the zebrafish ventral brain and floorplate requires cyclops/nodal signalling. Nature, 1998; 395:185–189.
39.
RebagliatiMR, ToyamaR, HaffterP, DawidIB. Cyclops encodes a nodal-related factor involved in midline signaling. Proc Natl Acad Sci U S A, 1998; 95:9932–9937.
40.
LuPN, LundC, KhuansuwanS, SchumannA, Harney-ToloM, GamseJT, et al.Failure in closure of the anterior neural tube causes left isomerization of the zebrafish epithalamus. Dev Biol, 2013; 374:333–344.
41.
LiangJO, EtheridgeA, HantsooL, RubinsteinAL, NowakSJ, Izpisua BelmonteJC, et al.Asymmetric nodal signaling in the zebrafish diencephalon positions the pineal organ. Development, 2000; 127:5101–5112.
42.
MathieuJ, BarthA, RosaFM, WilsonSW, PeyrierasN. Distinct and cooperative roles for Nodal and Hedgehog signals during hypothalamic development. Development, 2002; 129:3055–3065.
43.
HagosEG, FanX, DouganST. The role of maternal Activin-like signals in zebrafish embryos. Dev Biol, 2007; 309:245–258.
44.
PeiW, WilliamsPH, ClarkMD, StempleDL, FeldmanB. Environmental and genetic modifiers of squint penetrance during zebrafish embryogenesis. Dev Biol, 2007; 308:368–378.
45.
PeiW, FeldmanB. Identification of common and unique modifiers of zebrafish midline bifurcation and cyclopia. Dev Biol, 2009; 326:201–211.
46.
ChitramuthuBP, BennettHP. High resolution whole mount in situ hybridization within zebrafish embryos to study gene expression and function. J Vis Exp, 2013:e50644.
47.
ThisseB, ThisseC. In situ hybridization on whole-mount zebrafish embryos and young larvae. Methods Mol Biol, 2014; 1211:53–67.
48.
ThisseB, HeyerV, LuxA, AlunniA, DegraveA, SeiliezI, et al.Spatial and temporal expression of the zebrafish genome by large-scale in situ hybridization screening. Methods Cell Biol, 2004; 77:505–519.
49.
HagosEG, DouganST. Time-dependent patterning of the mesoderm and endoderm by Nodal signals in zebrafish. BMC Dev Biol, 2007; 7:22.
50.
ChowRL, LangRA. Early eye development in vertebrates. Annu Rev Cell Dev Biol, 2001; 17:255–296.
51.
ThisseC, ThisseB. Antivin, a novel and divergent member of the TGFbeta superfamily, negatively regulates mesoderm induction. Development, 1999; 126:229–240.
52.
SellerMJ, Perkins-ColeKJ. Hyperthermia and neural tube defects of the curly-tail mouse. J Craniofac Genet Dev Biol, 1987; 7:321–330.
53.
FinnellRH, MoonSP, AbbottLC, GoldenJA, ChernoffGF. Strain differences in heat-induced neural tube defects in mice. Teratology, 1986; 33:247–252.
54.
ZhangJ, ChenFZ, GaoQ, SunJH, TianGP, GaoYM. Hyperthermia induces upregulation of connexin43 in the golden hamster neural tube. Birth Defects Res A Clin Mol Teratol, 2012; 94:16–21.
55.
BuckiovaD, KubinovaL, SoukupA, JelinekR, BrownNA. Hyperthermia in the chick embryo: HSP and possible mechanisms of developmental defects. Int J Dev Biol, 1998; 42:737–740.
56.
BuckiovaD, BrownNA. Mechanism of hyperthermia effects on CNS development: rostral gene expression domains remain, despite severe head truncation; and the hindbrain/otocyst relationship is altered. Teratology, 1999; 59:139–147.
57.
GrippKW, WottonD, EdwardsMC, RoesslerE, AdesL, MeineckeP, et al.Mutations in TGIF cause holoprosencephaly and link NODAL signalling to human neural axis determination. Nat Genet, 2000; 25:205–208.
58.
BarrierM, DixDJ, MirkesPE. Inducible 70 kDa heat shock proteins protect embryos from teratogen-induced exencephaly: analysis using Hspa1a/a1b knockout mice. Birth Defects Res A Clin Mol Teratol, 2009; 85:732–740.
59.
GrayRS, RoszkoI, Solnica-KrezelL. Planar cell polarity: coordinating morphogenetic cell behaviors with embryonic polarity. Dev Cell, 2011; 21:120–133.
60.
UenoN, GreeneND. Planar cell polarity genes and neural tube closure. Birth Defects Res C Embryo Today, 2003; 69:318–324.
61.
TawkM, ArayaC, LyonsDA, ReugelsAM, GirdlerGC, BayleyPR, et al.A mirror-symmetric cell division that orchestrates neuroepithelial morphogenesis. Nature, 2007; 446:797–800.
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