ライフサイエンスコーパス: Lefty

1 diffusion rates of Nodal and its antagonist Lefty.

2 astula stage embryo, a process that requires lefty.

3 signaling, we validated the Nodal inhibitor Lefty.

4 the signaling gene nodal and its antagonist lefty.

5 ist squint and the TGF-beta Nodal antagonist lefty.

6 cular mechanisms underlying this function of Lefty.

7 ited, and include follistatin, Cerberus, and Lefty.

8 FN is also required for the expression of Lefty 1/2 and activation of SMADs 2 and 3 at the floor p

9 bryos, even in the absence of normal antivin/lefty-1 and Pitx2 expression, strongly suggests that hea

10 etry in lateral plate mesoderm (LPM) antivin/lefty-1 and Pitx2 expression.

11 demonstrate that retinoic acid (RA) controls Lefty-1 expression in a pathway downstream or parallel t

12 Expression of the left-specific gene Lefty-1 is absent in Shh(-/-) embryos, suggesting that t

13 In the absence of Smad5, lefty-1 was expressed at very low or undetectable levels

14 /- embryos, the expression of Ebaf (formerly lefty-1) in the left side of the floor plate and Leftb (

15 tivin receptor IIa, sonic hedgehog, Caronte, Lefty-1, and Fgf8 to be unaffected by the lack of retino

16 beta family signaling proteins (i.e., nodal, lefty-1, lefty-2, activin receptor type IIB, and Smad2)

17 rming growth factor-beta superfamily members Lefty-1, Lefty-2, and nodal comprise a regulatory pathwa

18 cient embryos, we examined the expression of lefty-1, lefty-2, nodal, and Pitx2 since the asymmetric

19 These data suggest that Smad5 is upstream of lefty-1, nodal, and lefty-2, and as a consequence also o

20 lecular interactions between Activin, FGF-8, Lefty-1, Nodal, BMPs and Car that cooperate to control l

21 y defects could be the result of the lack of Lefty-1.

22 h and RA pathways converge in the control of Lefty-1.

23 omized, and at earlier stages in development lefty-2 and nodal, which are normally expressed asymmetr

24 asymmetric patterns of expression of nodal, lefty-2 and Pitx2.

25 ally that left-sided expression of pitx2 and lefty-2 are also perturbed in Furin-deficient embryos.

26 side of the floor plate and Leftb (formerly lefty-2), nodal and Pitx2 in the left lateral plate meso

27 ly signaling proteins (i.e., nodal, lefty-1, lefty-2, activin receptor type IIB, and Smad2) in L-R ax

28 hat Smad5 is upstream of lefty-1, nodal, and lefty-2, and as a consequence also of Pitx2, and Smad5 i

29 wth factor-beta superfamily members Lefty-1, Lefty-2, and nodal comprise a regulatory pathway whose f

30 ery low or undetectable levels, while nodal, lefty-2, and Pitx2 were expressed bilaterally.

31 ryos, we examined the expression of lefty-1, lefty-2, nodal, and Pitx2 since the asymmetric expressio

32 The deduced amino acid sequences of LEFTY A and LEFTY B are more similar to each other than

33 rt characterization of two Lefty homologues, LEFTY A and LEFTY B, separated by approximately 50 kb on

34 LEFTY A is identical to ebaf, a cDNA previously identifi

35 e in the cysteine-knot region of the protein LEFTY A, and the phenotype of affected individuals is ve

36 mental pathways including those of TGF-beta (Lefty A, NMA, follistatin), homeo domain (HoxD1, Meis2,

37 ed one nonsense and one missense mutation in LEFTY A.

38 Here, we report on the effect of lefty, a novel member of the TGF-beta family, on the hom

39 show that TGF-beta signaling is inhibited by lefty, a novel member of the TGF-beta superfamily.

40 nodal and the inhibitors of Nodal signaling, lefty-A and lefty-B, are down-regulated very early upon

41 tivation of Smad2/3 and expression of nodal, lefty-A and lefty-B, while inhibition of ALK4/5/7 by the

42 K3-inhibitor, BIO, high expression of nodal, lefty-A, and lefty-B also requires activation of ALK4/5/

43 that ECM is a principal surface of Nodal and Lefty accumulation.

44 gesting cleavage to be an essential step for lefty activation.

45 ured the biophysical properties of the Nodal/Lefty activator/inhibitor system during zebrafish embryo

46 In particular, using a novel assay for Lefty activity in mammalian cell culture, we find that L

47 nge Nodal signal Cyclops is not regulated by Lefty activity.

48 cells do not express the inhibitor to Nodal, Lefty, allowing them to overexpress this embryonic morph

49 these signals, including the Nodal inhibitor Lefty, an atypical TGFbeta factor, are induced by Nodal.

50 by EGF-CFC cofactors and antagonists of the Lefty and Cerberus families of proteins, allowing precis

51 Xnr1/Nodal, together with inhibitors such as Lefty and Coco/Cerl2, have been shown to provide the sig

52 sion analysis demonstrates that a balance of lefty and cyclops signaling is required for normal mesen

53 teractions among co-expressed members of the lefty and nodal subfamilies of TGF-beta signaling molecu

54 ality of the viscera (cyclops/nodal, antivin/lefty and pitx2) are coexpressed on the left side of the

55 ings provide a new insight on the actions of lefty and suggest that this cytokine plays an active rol

56 n of the endogenous Nodal inhibitors Lefty2 (Lefty) and truncated Cerberus (Cerb-S) and by pharmacolo

57 on TGFbeta-related signals, including Nodal, Lefty, and BMPs.

58 C co-receptor Cripto and can be inhibited by Lefty antagonists.

59 The secreted TGFbeta factor Lefty antagonizes Nodal signaling during vertebrate embr

60 f discordant monozygotic twins suggests that lefties are one gene apart from righties.

61 llularly, the Nodal antagonists Cerberus and Lefty are permissive for ADMP activity.

62 asymmetric expression patterns of nodal and lefty are randomized in iv/iv embryos, suggesting that i

63 n contrast to earlier reports that nodal and lefty are upstream of pitx2, ectopic pitx2c in other reg

64 deduced amino acid sequences of LEFTY A and LEFTY B are more similar to each other than to Lefty1 or

65 ization of two Lefty homologues, LEFTY A and LEFTY B, separated by approximately 50 kb on chromosome

66 BIO, high expression of nodal, lefty-A, and lefty-B also requires activation of ALK4/5/7.

67 e inhibitors of Nodal signaling, lefty-A and lefty-B, are down-regulated very early upon differentiat

68 Smad2/3 and expression of nodal, lefty-A and lefty-B, while inhibition of ALK4/5/7 by the kinase inhi

69 h a striking conservation of the inhibitors, Lefties, but differential targeting of the activators, N

70 Fibroblastic cells forced to express lefty by retroviral transduction lost their ability to d

71 eceptor, Acvr2b, and to the Nodal inhibitor, Lefty, by fluorescence cross-correlation spectroscopy.

72 Furthermore, Lefty can also interact with EGF-CFC proteins and preven

73 First, Lefty can block Nodal signaling at a distance.

74 vity in mammalian cell culture, we find that Lefty can inhibit signaling by Nodal but not by Activin

75 We show that Lefty can interact with Nodal in solution and thereby bl

76 PC cleavage in the lefty protein allowed the lefty cleavage sites to be identified.

77 This suggests that Lefty-dependent modulation of organizer signaling might

78 Lefty did not induce Smad2 or Smad5 phosphorylation, Sma

79 The action of lefty does not appear to depend on protein synthesis, in

80 ypoblast, and finally a late inhibition from Lefty emitted by the primitive streak itself.

81 is directly associated with the secretion of Lefty, exclusive to hESCs, because it is not detected in

82 Differentiating EBs derived from Lefty expressing hESCs generated a dense network of beta

83 beta-tubulin III positive neurites, and when Lefty expressing hESCs were grown as a monolayer and all

84 ants can be rescued by ectopic expression of lefty far from its normal expression domain or by spatia

85 ssing of the lefty polypeptide to the 28-kDa lefty form.

86 and biochemical analysis showed transfer of Lefty from left LPM to right LPM, providing direct evide

87 Moreover, reduction in Lefty gene expression is linked to elevated DNA methylat

88 In mouse, lefty genes play critical roles in the left-right (L-R)

89 Analysis of Nodal and Lefty gradients revealed that Nodals have a shorter rang

90 s fluorescence recovery assays revealed that Leftys have a higher effective diffusion coefficient tha

91 -labeling analysis indicated that Nodals and Leftys have similar clearance kinetics, whereas fluoresc

92 We now report characterization of two Lefty homologues, LEFTY A and LEFTY B, separated by appr

93 nism by Car induces asymmetric expression of Lefty in the midline, preventing spread of left-sided si

94 Similarly, lefty inhibited both BMP-mediated Smad5 phosphorylation

95 Moreover, lefty inhibited the events that lie downstream from R-Sm

96 e diffusion coefficient of Nodal ligands and Lefty inhibitors in live zebrafish embryos by fluorescen

97 Nodal (here, Xnr1 or Nodal1 in Xenopus) and Lefty interact in a cross-regulatory relationship in mes

98 iding direct evidence that left-side-derived Lefty is a significant influence in ensuring the continu

99 derm inducer Nodal to activate its inhibitor Lefty is required for development.

100 cells to a hESC microenvironment (containing Lefty) leads to a dramatic down-regulation in their Noda

101 in LPM, and corresponding loss of downstream Lefty (lft1 and lft) expression, and aberrant brain and

102 e developmental signalling factors Nodal and Lefty may provide a real example of the kind of reaction

103 ct is not localized, and hence refractory to Lefty-mediated enforcement of localization.

104 We detected Lefty moving faster than Nodal, with evidence that intac

105 Protection of squint or lefty mRNAs from miR-430 resulted in enhanced or reduced

106 thout feedback: Lethal patterning defects in lefty mutants can be rescued by ectopic expression of le

107 We find that zebrafish lefty mutants exhibit excess Nodal signaling and increas

108 We hypothesized that Lefty mutations may be associated with human LR-axis mal

109 linked to elevated DNA methylation, as both Lefty-Nodal signalling and normal morphogenesis are larg

110 ated oxidation of 5-methylcytosine modulates Lefty-Nodal signalling by promoting demethylation in opp

111 data also provide insights into the way that lefty/nodal signals interact in the initiation of differ

112 Simultaneous protection of squint and lefty or absence of miR-430 caused an imbalance and redu

113 EBs derived from either Lefty or Cerb-S expressing hESCs also contained a greate

114 s, embryoid bodies (EBs) derived from either Lefty or Cerb-S overexpressing hESCs showed increased ex

115 tments reproduced the neuralising effects of Lefty overexpression in hESCs.

116 Lefty perturbed TGF-beta signaling by inhibiting the pho

117 a, which eventually induces asymmetric Nodal/Lefty/Pitx2 expression on the left side of the lateral p

118 PCs showed activity in the processing of the lefty polypeptide to the 28-kDa lefty form.

119 Lefty polypeptides, novel members of the transforming gr

120 inducing MAPK activity, indicating that the lefty precursor is biologically active.

121 prevented the proteolytic processing of the lefty precursor to the 34- and 28-kDa forms, respectivel

122 tion analysis showed that PC5A processed the lefty precursor to the 34-kDa form in vivo, whereas furi

123 bryonic laterality, we studied their role in lefty processing.

124 By expressing Xnr1 and Lefty proproteins that produce mature functional epitope

125 e consensus sequences for PC cleavage in the lefty protein allowed the lefty cleavage sites to be ide

126 Surprisingly, the 42-kDa lefty protein was also capable of inducing MAPK activity

127 It is currently thought that Lefty proteins act as feedback inhibitors of Nodal signa

128 te mesendoderm induction in vertebrates, and Lefty proteins antagonize it.

129 Nodal and Lefty proteins belong to divergent subfamilies of the TG

130 esults provide mechanistic insights into how Lefty proteins can achieve efficient and stringent regul

131 s in zebrafish and frogs have suggested that Lefty proteins can act as long-range inhibitors for Noda

132 distinct and unexpected mechanisms by which Lefty proteins can antagonize Nodal activity.

133 We present three lines of evidence that Lefty proteins diminish the range of Squint signaling by

134 These results indicate that Lefty proteins restrict the activity range of Nodal sign

135 vealed that Nodals have a shorter range than Lefty proteins.

136 which Squint induces mesoderm is reduced by Lefty proteins.

137 Thus, lefty provides a repressed state of TGF-beta- or BMP-res

138 ajor determinant of the differences in Nodal/Lefty range and provide biophysical support for reaction

139 Second, Lefty regulates the range of Squint signaling before reg

140 Here, we characterize the Xenopus lefty-related factor antivin (Xatv).

141 Lefty repressed TGF-beta-induced expression of reporter

142 Third, Lefty restricts the range of Squint activity in squint m

143 We also find that Lefty restricts the response to both high and low levels

144 Transfection of different cell lines with lefty resulted in expression of a 42-kDa protein, which

145 on of Smad2/3 binding at the Nodal inhibitor lefty, resulting in direct repression of lefty that is c

146 patterning is directed by a conserved nodal/lefty signaling cascade on the left side of the embryo,

147 processing as a mechanism for regulation of lefty signaling.

148 ing vertebrate embryogenesis, members of the Lefty subclass of Transforming Growth Factor-beta (TGFbe

149 The Lefty subfamily of TGFbeta signaling molecules has been

150 tor lefty, resulting in direct repression of lefty that is critical for mesendoderm specification.

151 In addition, lefty transduction significantly decreased collagen type

152 efty, which arises mainly from repression of Lefty translation by the microRNA miR-430.

153 tive form of lefty, we studied the effect of lefty treatment on pluripotent P19 cells.

154 Nodal and lefty, two genes that are normally expressed only in the

155 other components of this cascade (Nodal and Lefty) was unchanged after blocking N-cadherin function,

156 To identify the biologically active form of lefty, we studied the effect of lefty treatment on pluri

157 differentially timed production of Nodal and Lefty, which arises mainly from repression of Lefty tran

158 Lefty, which is normally also expressed in the floorplat

159 enes (Xnrs) by extracellular Xenopus antivin/lefty (Xatv/Xlefty)-mediated functional antagonism and B

160 We propose that the induction of lefty/Xatv in the left LPM by nodal/Xnr1 provides an eff

161 Here, Xenopus Lefty (Xlefty) function was blocked by injection of anti

162 Here, we show that Xenopus lefty (Xlefty) is expressed both bilaterally in symmetri