Bmp and Nodal Independently Regulate Expression to Maintain Unilateral Nodal Activity during Left-Right Axis Specification in Zebrafish
In vertebrates, left-right (LR) axis specification is determined by a ciliated structure in the posterior region of the embryo. Fluid flow in this ciliated structure is responsible for the induction of unilateral left-sided Nodal activity in the lateral plate mesoderm, which in turn regulates organ laterality. Bmp signalling activity has been implied in repressing Nodal expression on the right side, however its mechanism of action has been controversial. In a forward genetic screen for mutations that affect LR patterning, we identified the zebrafish linkspoot (lin) mutant, characterized by cardiac laterality and mild dorsoventral patterning defects. Mapping of the lin mutation revealed an inactivating missense mutation in the Bmp receptor 1aa (bmpr1aa) gene. Embryos with a mutation in lin/bmpr1aa and a novel mutation in its paralogue, bmpr1ab, displayed a variety of dorsoventral and LR patterning defects with increasing severity corresponding with a decrease in bmpr1a dosage. In Bmpr1a-deficient embryos we observed bilateral expression of the Nodal-related gene, spaw, coupled with reduced expression of the Nodal-antagonist lefty1 in the midline. Using genetic models to induce or repress Bmp activity in combination with Nodal inhibition or activation, we found that Bmp and Nodal regulate lefty1 expression in the midline independently of each other. Furthermore, we observed that the regulation of lefty1 by Bmp signalling is required for its observed downregulation of Nodal activity in the LPM providing a novel explanation for this phenomenon. From these results we propose a two-step model in which Bmp regulates LR patterning. Prior to the onset of nodal flow and Nodal activation, Bmp is required to induce lefty1 expression in the midline. When nodal flow has been established and Nodal activity is apparent, both Nodal and Bmp independently are required for lefty1 expression to assure unilateral Nodal activation and correct LR patterning.
Vyšlo v časopise:
Bmp and Nodal Independently Regulate Expression to Maintain Unilateral Nodal Activity during Left-Right Axis Specification in Zebrafish. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002289
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002289
Souhrn
In vertebrates, left-right (LR) axis specification is determined by a ciliated structure in the posterior region of the embryo. Fluid flow in this ciliated structure is responsible for the induction of unilateral left-sided Nodal activity in the lateral plate mesoderm, which in turn regulates organ laterality. Bmp signalling activity has been implied in repressing Nodal expression on the right side, however its mechanism of action has been controversial. In a forward genetic screen for mutations that affect LR patterning, we identified the zebrafish linkspoot (lin) mutant, characterized by cardiac laterality and mild dorsoventral patterning defects. Mapping of the lin mutation revealed an inactivating missense mutation in the Bmp receptor 1aa (bmpr1aa) gene. Embryos with a mutation in lin/bmpr1aa and a novel mutation in its paralogue, bmpr1ab, displayed a variety of dorsoventral and LR patterning defects with increasing severity corresponding with a decrease in bmpr1a dosage. In Bmpr1a-deficient embryos we observed bilateral expression of the Nodal-related gene, spaw, coupled with reduced expression of the Nodal-antagonist lefty1 in the midline. Using genetic models to induce or repress Bmp activity in combination with Nodal inhibition or activation, we found that Bmp and Nodal regulate lefty1 expression in the midline independently of each other. Furthermore, we observed that the regulation of lefty1 by Bmp signalling is required for its observed downregulation of Nodal activity in the LPM providing a novel explanation for this phenomenon. From these results we propose a two-step model in which Bmp regulates LR patterning. Prior to the onset of nodal flow and Nodal activation, Bmp is required to induce lefty1 expression in the midline. When nodal flow has been established and Nodal activity is apparent, both Nodal and Bmp independently are required for lefty1 expression to assure unilateral Nodal activation and correct LR patterning.
Zdroje
1. RamsdellAF 2005 Left-right asymmetry and congenital cardiac defects: getting to the heart of the matter in vertebrate left-right axis determination. Dev Biol 288 1 20
2. BamfordRNRoesslerEBurdineRDSaplakoğluUdela CruzJ 2000 Loss-of-function mutations in the EGF-CFC gene CFC1 are associated with human left-right laterality defects. Nat Genet 26 365 369
3. KuehlKSLoffredoC 2002 Risk factors for heart disease associated with abnormal sidedness. Teratology 66 242 248
4. GrandeCPatelNH 2009 Nodal signalling is involved in left-right asymmetry in snails. Nature 457 1007 1011
5. LongSAhmadNRebagliatiM 2003 The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry. Development 130 2303 2316
6. SchierAF 2009 Nodal morphogens. Cold Spring Harb Perspect Biol 1 a003459
7. MenoCItoYSaijohYMatsudaYTashiroK 1997 Two closely-related left-right asymmetrically expressed genes, lefty-1 and lefty-2: their distinct expression domains, chromosomal linkage and direct neuralizing activity in Xenopus embryos. Genes Cells 2 513 524
8. ThisseBPflumioSFurthauerMLoppinBHeyerV 2001 Expression of the zebrafish genome during embryogenesis. ZFIN Direct Data Submission
9. MenoCShimonoASaijohYYashiroKMochidaK 1998 lefty-1 is required for left-right determination as a regulator of lefty-2 and nodal. Cell 94 287 297
10. NakamuraTMineNNakaguchiEMochizukiAYamamotoM 2006 Generation of robust left-right asymmetry in the mouse embryo requires a self-enhancement and lateral-inhibition system. Dev Cell 11 495 504
11. MeinhardtHGiererA 2000 Pattern formation by local self-activation and lateral inhibition. Bioessays 22 753 760
12. ChangHZwijsenAVogelHHuylebroeckDMatzukMM 2000 Smad5 is essential for left-right asymmetry in mice. Dev Biol 219 71 78
13. ChocronSVerhoevenMCRentzschFHammerschmidtMBakkersJ 2007 Zebrafish Bmp4 regulates left-right asymmetry at two distinct developmental time points. Dev Biol 305 577 588
14. FujiwaraTDehartDBSulikKKHoganBLM 2002 Distinct requirements for extra-embryonic and embryonic bone morphogenetic protein 4 in the formation of the node and primitive streak and coordination of left-right asymmetry in the mouse. Development 129 4685 4696
15. FurtadoMBSollowayMJJonesVJCostaMWBibenC 2008 BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4. Genes & Development 22 3037 3049
16. KishigamiSYoshikawaS-ICastranioTOkazakiKFurutaY 2004 BMP signaling through ACVRI is required for left-right patterning in the early mouse embryo. Dev Biol 276 185 193
17. MineNAndersonRMKlingensmithJ 2008 BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment. Development 135 2425 2434
18. Monsoro-BurqALe DouarinNM 2001 BMP4 plays a key role in left-right patterning in chick embryos by maintaining Sonic Hedgehog asymmetry. Mol Cell 7 789 799
19. PiedraMERosMA 2002 BMP signaling positively regulates Nodal expression during left right specification in the chick embryo. Development 129 3431 3440
20. Rodríguez EstebanCCapdevilaJEconomidesANPascualJOrtizA 1999 The novel Cer-like protein Caronte mediates the establishment of embryonic left-right asymmetry. Nature 401 243 251
21. SchlangeTArnoldH-HBrandT 2002 BMP2 is a positive regulator of Nodal signaling during left-right axis formation in the chicken embryo. Development 129 3421 3429
22. YokouchiYVoganKJPearseRVTabinCJ 1999 Antagonistic signaling by Caronte, a novel Cerberus-related gene, establishes left-right asymmetric gene expression. Cell 98 573 583
23. ShiYMassaguéJ 2003 Mechanisms of TGF-ß signaling from cell membrane to the nucleus. Cell 113 685 700
24. GuZReynoldsEMSongJLeiHFeijenA 1999 The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo. Development 126 2551 2561
25. MishinaYCrombieRBradleyABehringerRR 1999 Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis. Dev Biol 213 314 326
26. MishinaYSuzukiAUenoNBehringerRR 1995 Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes & Development 9 3027 3037
27. ZhuLMarvinMJGardinerALassarABMercolaM 1999 Cerberus regulates left-right asymmetry of the embryonic head and heart. Curr Biol 9 931 938
28. MullinsMCHammerschmidtMKaneDAOdenthalJBrandM 1996 Genes establishing dorsoventral pattern formation in the zebrafish embryo: the ventral specifying genes. Development 123 81 93
29. BauerHLeleZRauchGJGeislerRHammerschmidtM 2001 The type I serine/threonine kinase receptor Alk8/Lost-a-fin is required for Bmp2b/7 signal transduction during dorsoventral patterning of the zebrafish embryo. Development 128 849 858
30. SchillingTFConcordetJPInghamPW 1999 Regulation of left-right asymmetries in the zebrafish by Shh and BMP4. Dev Biol 210 277 287
31. LittleSCMullinsMC 2009 Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat Cell Biol 11 637 643
32. KishimotoYLeeKHZonLHammerschmidtMSchulte-MerkerS 1997 The molecular nature of zebrafish swirl: BMP2 function is essential during early dorsoventral patterning. Development 124 4457 4466
33. SchultheissTMBurchJBLassarAB 1997 A role for bone morphogenetic proteins in the induction of cardiac myogenesis. Genes & Development 11 451 462
34. SmithKAChocronSvon der HardtSde PaterESoufanA 2008 Rotation and asymmetric development of the zebrafish heart requires directed migration of cardiac progenitor cells. Dev Cell 14 287 297
35. van RooijenEGilesRHVoestEEvan RooijenCSchulte-MerkerS 2008 LRRC50, a conserved ciliary protein implicated in polycystic kidney disease. J Am Soc Nephrol 19 1128 1138
36. YamamotoMMineNMochidaKSakaiYSaijohY 2003 Nodal signaling induces the midline barrier by activating Nodal expression in the lateral plate. Development 130 1795 1804
37. InmanGJNicolásFJCallahanJFHarlingJDGasterLM 2002 SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 62 65 74
38. WangXYostHJ 2008 Initiation and propagation of posterior to anterior (PA) waves in zebrafish left-right development. Dev Dyn 237 3640 3647
39. FeldmanBConchaMLSaúdeLParsonsMJAdamsRJ 2002 Lefty antagonism of Squint is essential for normal gastrulation. Curr Biol 12 2129 2135
40. SaijohYOkiSOhishiSHamadaH 2003 Left-right patterning of the mouse lateral plate requires nodal produced in the node. Dev Biol 256 161 173
41. Martínez-BarberáJPToressonHDa RochaSKraussS 1997 Cloning and expression of three members of the zebrafish Bmp family: Bmp2a, Bmp2b and Bmp4. Gene 198 53 59
42. ChenJNvan BebberFGoldsteinAMSerlucaFCJacksonD 2001 Genetic steps to organ laterality in zebrafish. Comp Funct Genomics 2 60 68
43. ChenJNvan EedenFJWarrenKSChinANüsslein-VolhardC 1997 Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish. Development 124 4373 4382
44. WienholdsE 2003 Efficient Target-Selected Mutagenesis in Zebrafish. Genome Research 13 2700 2707
45. ThisseCThisseB 2008 High-resolution in situ hybridization to whole-mount zebrafish embryos. Nat Protoc 3 59 69
46. von der HardtSBakkersJInbalACarvalhoLSolnica-KrezelL 2007 The Bmp gradient of the zebrafish gastrula guides migrating lateral cells by regulating cell-cell adhesion. Curr Biol 17 475 487
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 9
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- The Evolutionarily Conserved Longevity Determinants HCF-1 and SIR-2.1/SIRT1 Collaborate to Regulate DAF-16/FOXO
- Genome-Wide Analysis of Heteroduplex DNA in Mismatch Repair–Deficient Yeast Cells Reveals Novel Properties of Meiotic Recombination Pathways
- Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD
- MicroRNA Predictors of Longevity in