Bmp and Nodal Independently Regulate lefty1 Expression to Maintain Unilateral Nodal Activity during Left-Right Axis Specification in Zebrafish 英文参考文献.docVIP

BmpandNodalIndependentlyRegulatelefty1 ExpressiontoMaintainUnilateralNodalActivityduring Left-RightAxisSpecificationinZebrafish KellyA.Smith1.¤,EmilyNoe¨l1.,IngridThurlings1,HolgerRehmann2,SonjaChocron1,JeroenBakkers1,3* 1Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, The Netherlands, 2University Medical CenterUtrecht,Utrecht,TheNetherlands,3InteruniversityCardiologyInstituteoftheNetherlands,Utrecht,TheNetherlands Abstract Invertebrates,left-right(LR)axisspecificationisdeterminedbyaciliatedstructureintheposteriorregionoftheembryo. Fluidflowinthisciliatedstructureisresponsiblefortheinductionofunilateralleft-sidedNodalactivityinthelateralplate mesoderm,whichinturnregulatesorganlaterality.BmpsignallingactivityhasbeenimpliedinrepressingNodalexpression ontherightside,howeveritsmechanismofactionhasbeencontroversial.Inaforwardgeneticscreenformutationsthat 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 bmpr1adosage.InBmpr1a-deficientembryosweobservedbilateralexpressionoftheNodal-relatedgene,spaw ,coupled with reduced expression of the Nodal-antagonist lefty1 in the midline. Using genetic models to induce or repress Bmp activityincombinationwithNodalinhibitionoractivation,wefoundthatBmpandNodalregulatelefty1expressioninthe midlineindependentlyofeachother.Furthermore,weobservedthattheregulationoflefty1byBmpsignallingisrequired for its observed downregulation of Nodal activity in the LPMproviding anovel explanation for this phenomenon. From these results wepropose a two-step modelin w