ライフサイエンスコーパス: notum

1 tinguish the future wing from the body wall (notum).

2 teroposterior axis of the Drosophila thorax (notum).

3 idia in the eye, and sensory bristles on the notum.

4 uch, but grow normally in the wing hinge and notum.

5 veins in the wing and of macrochaete in the notum.

6 neural structures in the eye, wing, leg and notum.

7 rning sensory precursor cells in the lateral notum.

8 velopment of sensory bristles in the lateral notum.

9 ensory bristles in the lateral domain of the notum.

10 organ precursor cells of the wing margin or notum.

11 st suggested increased lipolysis capacity by NOTUM.

12 for experimental validation as inhibitors of Notum.

13 fit-for-purpose small molecule inhibitors of Notum.

14 IM-HD transcription factor-in the developing notum.

15 suggesting enhanced thermogenic capacity by NOTUM.

16 shown to bind in the palmitoleate pocket of Notum.

17 n restriction of JAK/STAT signaling from the notum.

18 tivation of Wnt signaling in the presence of Notum.

19 of the hinge, and restricts expansion of the notum.

20 relative expansion of the pouch, hinge, and notum.

21 , the hinge, the surrounding pleura, and the notum.

22 romised wing growth and the formation of the notum.

23 mediate activation at specific sites on the notum.

24 is specific to Notum 2, as overexpression of Notum 1a does not affect PMN axon trajectory.

25 Notum 1a does not interact with Glypican 4, an essential

26 Our work shows that zebrafish Notum 1a, an ortholog of mammalian Notum, contributes to

27 While homologs of Notum, including zebrafish Notum 1a, negatively regulate the Wnt/beta-catenin signa

28 Ectopic expression of Notum 2 by cells contacting the growing CaP axon induced

29 ency of branching, suggesting that localized Notum 2 expression affects axon behavior.

30 We propose a model where Notum 2 expression at the MPs provides a cue to release

31 g pathway, we discovered a novel function of Notum 2 in regulating motor axon guidance.

32 In contrast, mosaic Notum 2 overexpression induced branching of PMN axons.

33 Knockdown of Notum 2 resulted in a failure of caudal primary (CaP) ax

34 This effect is specific to Notum 2, as overexpression of Notum 1a does not affect P

35 new member of the Notum family in zebrafish, Notum 2, which is expressed exclusively in the MPs durin

36 otum, palmitoleoyl-protein carboxylesterase (NOTUM), a negative regulator of canonical WNT signaling,

37 It does, however, require Notum, a conserved secreted feedback inhibitor of Wnt si

38 This is achieved in part by Notum, a highly conserved secreted feedback antagonist.

39 , at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palm

40 We recently showed that NOTUM, a liver-secreted Wnt inhibitor, can acutely promo

41 We further show that Notum, a negative regulator of Wg signaling, downregulat

42 In Drosophila, Notum, a secreted alpha/beta-hydrolase, antagonizes the

43 Follistatin and Notum, a Wnt inhibitor, are mutually required to reestab

44 Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expan

45 m polarization, which opposes injury-induced notum-activating Wnt/beta-catenin signals and regulates

46 tudinal muscle after injury for preferential notum activation at anterior-facing wounds are poorly un

47 This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molec

48 new approach to treat disease where aberrant Notum activity has been identified as the underlying cau

49 ld be of use in diseases where dysfunctional Notum activity is an underlying cause.

50 Inhibition of Notum activity may represent a new approach to treat dis

51 selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models

52 ural biology identified potent inhibitors of Notum activity that restored Wnt/B-catenin signaling in

53 ural biology identified potent inhibitors of Notum activity that restored Wnt/beta-catenin signaling

54 copied by Wg overexpression, suggesting that Notum acts solely by inhibiting Wg trans-synaptic signal

55 ally, as well as its homolog dally-like, and notum affect Wingless distribution in the embryonic epid

56 Here, we reveal that, in Drosophila pupal notum, alteration of the bi- or tricellular septate junc

57 We show that in each row of the notum, an anteromedial located central SOP divides first

58 o elicits a similar peripheral expression of Notum, an enzyme that limits the extent of Wg signaling.

59 ntaining Wnt signalling due to production of Notum, an extracellular Wnt inhibitor, in aged Paneth ce

60 y, stat92E activity is down regulated in the notum and distal pouch.

61 scs vn is first expressed in the presumptive notum and later in the wing-pouch and hinge regions.

62 activity of the E(spl)mgamma enhancer in the notum and margin territories of the wing disc can be ove

63 r embryonic segmentation, development of the notum and wing margin, and photoreceptor differentiation

64 ic EGFR hyperactivity phenotypes in the eye, notum and wing, and also leads to downregulation of Yan,

65 ired for expression of polarity determinants notum and wnt1 and for correct patterning of the structu

66 ior versus posterior pole identities through notum and wnt1 signaling, and two Wnt/FGFRL signaling pa

67 ters of the developing sensory organs in the notum, and are regulated by the signalling molecules Win

68 e identified three interacting genes: dally, notum, and brahma.

69 nly the mechanosensory bristles on the head, notum, and scutellum are affected by warthog mutations.

70 gies are available to identify inhibitors of Notum, and structural studies are accelerating the disco

71 thorax but also broadly contiguous with the notum anteriorly and posteriorly (details unobservable i

72 We identify NOTUM as a key mediator during the early stages of mutat

73 Here, we use bristle patterning in the fly notum as a model system to explore the regulatory and fu

74 Here we use the fly notum as a model system to identify a novel process of c

75 rmation of the insect wing from the thoracic notum as well as the already known pleural elements of t

76 rting their overall origin from the thoracic notum as well as the expected medial, pleural series of

77 ntified processes required for wound-induced notum asymmetry.

78 Furthermore, NOTUM attenuated WNT3A's effects on upregulation of TGF-

79 ncode several secreted WNT antagonists, with Notum being the most highly expressed.

80 1) Vn/EGFR signaling directs cells to become notum by antagonizing wing development and by activating

81 in ageing and demonstrate that targeting of Notum can promote regeneration of aged tissues.

82 signaling, especially through inhibition of Notum carboxylesterase activity.

83 These insights into Notum catalytic inhibition may guide development of more

84 A subset of the trichome-producing notum cells differentiate as "tendon cells," serving as

85 roquois Complex (Iro-C) genes in prospective notum cells, rendering them distinct from, and immiscibl

86 mplex (Iro-C) gene expression in prospective notum cells.

87 zebrafish Notum 1a, an ortholog of mammalian Notum, contributes to a self-regulatory loop that restri

88 enetic interaction studies show that dlp and Notum cooperate to restrict Wg signaling.

89 We suggest that Notum could amplify local differences in Wingless signal

90 Inhibitors of Notum could be of use in diseases where dysfunctional No

91 y the Tiki protease in the Organizer and the Notum deacylase in presumptive neuroectoderm orchestrate

92 essed the growth of wild-type organoids in a NOTUM-dependent manner.

93 In turn, injury-induced notum dictates polarization used in the next round of re

94 wn to be likely not to involve a gradient in Notum distribution, even though Notum is only expressed

95 Notum encodes a secreted protein that also limits Wg dis

96 ck inhibition between wnt11-6/wntA/wnt4a and notum, encoding conserved antagonistic signaling factors

97 lose two new chemical scaffolds that inhibit Notum enzymatic activity.

98 roposterior planar polarization requires the notum epithelia to balance mechanical stress generated b

99 Here we show that in the Drosophila notum epithelium, each cell division is associated with

100 hicine or nocodazole treatment) show ectopic notum expression at posterior-facing wounds.

101 notum expression is itself controlled by Wnt signaling,

102 ), and lowered PPAR-alpha activity increased Notum expression.

103 egative interactions between Stat92E and the notum factor Araucan, resulting in restriction of JAK/ST

104 We have identified a new member of the Notum family in zebrafish, Notum 2, which is expressed e

105 Muscle expression of notum, follistatin, evi/wls, glypican-1 and junctophilin

106 er among the down-regulated genes in the AAV-Notum group, suggesting a potential mechanism contributi

107 of beige/brown adipocyte markers in the AAV-Notum group, suggesting enhanced thermogenic capacity by

108 Notum has been thought to act as a phospholipase, sheddi

109 e organization of bristles on the Drosophila notum has long served as a popular model of robust tissu

110 and specific roles in the development of the notum, hinge, longitudinal vein 4, and all intervein reg

111 s work demonstrates an unexpected role for a Notum homolog in regulating growth cone migration, separ

112 from the well established functions of other Notum homologs in Wnt signaling.

113 nd FZDs involved in WNT reception and to the NOTUM hydrolase, which antagonizes WNTs by lipid moiety

114 The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Int

115 Here, we report that Notum hydrolyzes the Wnt palmitoleoylate adduct extracel

116 o specify dorsal pleura identity and inhibit notum identity to properly subdivide the body wall.

117 t library of 250 acids for screening against Notum in a biochemical assay followed by structure deter

118 at restored Wnt signaling in the presence of Notum in a cell-based reporter assay.

119 Activation of NOTUM in EVT cells is driven, at least in part, by endot

120 report studies of chronic overexpression of NOTUM in liver indicating that it protects against diet-

121 e asymmetric activation of the Wnt inhibitor notum in longitudinal body-wall muscle cells, preferenti

122 Moreover, pharmacological inhibition of Notum in mice enhanced the regenerative capacity of aged

123 rypts over time by using APC specific marker NOTUM in situ hybridization.

124 esults suggest a surprising specific role of Notum in the developing vertebrate embryo.

125 ectors were used to overexpress GFP or mouse Notum in the livers of male C57BL/6J mice and the mice w

126 The role of Notum in the setup of the Wg gradient is also shown to b

127 specificity in cell culture, but the role of Notum in vertebrate development has not been studied.

128 ary chemical tools for exploring the role of Notum in Wnt signaling.

129 While homologs of Notum, including zebrafish Notum 1a, negatively regulate

130 the spatial expression of these genes on the notum increased in the lineage leading to the higher Dip

131 Studies of mammalian Notum indicate promiscuous target specificity in cell cu

132 pendent manner to orient the polarization of notum induced by wounding.

133 Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown t

134 High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduc

135 e series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS

136 Notum inhibitors can restore Wnt signaling which may be

137 identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters

138 ibition may guide development of more potent Notum inhibitors.

139 d, and double-RNAi experiments indicate that notum inhibits Wnt signaling to promote head regeneratio

140 ometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential pa

141 Notum is a carboxylesterase that suppresses Wnt signalin

142 Carboxylesterase Notum is a negative regulator of the Wnt signaling pathw

143 Notum is a negative regulator of Wnt signaling acting th

144 These findings suggest that Notum is a prerequisite for the "default" neural fate an

145 Notum is a secreted Wnt antagonist that belongs to the a

146 Thus, Notum is a Wnt deacylase, and palmitoleoylation is oblig

147 typed arrangement of sensory bristles on the notum is determined by the tightly regulated control of

148 Notum is expressed in naive ectoderm and neural plate in

149 gradient in Notum distribution, even though Notum is only expressed close to the source of Wg synthe

150 f canonical WNT signaling via the actions of NOTUM is required for optimal EVT cell differentiation.

151 Wound-induced notum is specific to longitudinal (anterior-posterior-ax

152 notum is wound induced at anterior-facing planarian woun

153 incides temporally with that of ac-sc in the notum, is Wingless (Wg; also known as Wnt).

154 new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.

155 high fat, high sucrose diet feeding, the AAV-Notum mice exhibited decreased obesity and improved gluc

156 e epididymal white adipose tissue of the AAV-Notum mice were significantly reduced, suggesting decrea

157 Overall, our data suggest that NOTUM modulates adipose tissue function by promoting the

158 evels in Notum null mutants, indicating that Notum normally functions to coordinate synaptic structur

159 signaling 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], ME

160 In Notum null flies, we find upregulated extracellular Wg l

161 essed by genetically correcting Wg levels in Notum null mutants, indicating that Notum normally funct

162 macrochaete (sense organ) patterning on the notum of Drosophila melanogaster.

163 d sensory organ precursor (SOP) cells on the notum of some but not all flies.

164 Genetic targeting of Notum or Wnt supplementation restored function of aged i

165 This requires the polarity determinant notum Our work establishes planarians as a suitable mode

166 Notum, palmitoleoyl-protein carboxylesterase (NOTUM), a

167 ng 18], PZP [pregnancy zone protein], NOTUM [notum, palmitoleoyl-protein carboxylesterase], METAP1 [m

168 ere is an emerging understanding of the role Notum plays in disease, supporting the need to discover

169 There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer

170 cal Wnt11 and Dishevelled pathway regulating notum polarization, which opposes injury-induced notum-a

171 ding elicits expression of the Wnt inhibitor notum preferentially at anterior-facing wounds.

172 l (DV) compartments and limb-body wall (wing-notum) primordia depends on Epidermal Growth Factor Rece

173 compartments and limb (wing) and body wall (notum) primordia.

174 studies demonstrated that recombinant human NOTUM protein blocked the inhibitory effects of WNT3A on

175 as myofibroblasts secrete the Wnt inhibitor, NOTUM, providing spatial patterning.

176 axis of the dorsal mesothoracic segment: the notum, proximal wing, and wing blade.

177 provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but

178 ing in posterior and anterior regions of the notum, respectively.

179 uscular junction (NMJ) synapse, we find that Notum secreted from the postsynaptic muscle acts to stro

180 Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the

181 structive role in organizing the DV and wing-notum segregations, implying the existance of other loca

182 ssed mir-279/996 cluster, with a majority of notum sensory organs exhibiting transformation of sheath

183 Wnt/Notum signaling tunes numbers of differentiated brain ce

184 ganoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype,

185 agonizing wing development and by activating notum-specifying genes; (2) Vn/EGFR signaling directs ce

186 e present evidence that both the DV and wing-notum subdivisions are specified by activation of the Dr

187 he Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank i

188 chas is expressed in notum tendon cells, and its loss of function disturbs ce

189 MyosinII to modulate the mechanoresponse of notum tendon cells.

190 ngless produce a negative signal (encoded by notum) that inhibits Wingless signaling in nearby cells.

191 The Drosophila notum, the dorsal body wall of the thorax, is subdivided

192 gs representing an extension of the thoracic notum, the other stating that they are appendicular deri

193 t establishes a proximal appendage fate over notum, then the downstream response changes to direct th

194 binding sites on Notum, which probably help Notum to co-localize with Wnt proteins.

195 activation of N-driven Wg signaling leads to notum-to-wing transdetermination.

196 Here, we show that wounds in the Drosophila notum trigger cytoplasmic calcium increase by activating

197 When expressed in the notum, truncated Mam results in failure of lateral inhib

198 Notum was recently shown to act as a negative regulator

199 Furthermore, NOTUM was required for optimal human TS cell differentia

200 Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt si

201 Only one gene, notum, was differentially expressed early between anteri

202 in mechanically distinct regions of the fly notum, we find that the ability of cells to properly reo

203 etal regulators in the developing Drosophila notum, we have identified a critical role for Cdc42-aPKC

204 as mediated by direct inhibition of Axin and Notum, which encode essential, negatively acting compone

205 Bmp2/4 dorsally caused ectopic expression of Notum, which marks the ventral sucker field, and ectopic

206 es reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt

207 ions of the secreted extracellular deacylase Notum, which restricts Wg signaling by cleaving an essen

208 structive EGFR signal(s), in contrast to the notum-wing boundary, which continues to be defined by EG

209 Inhibition of notum with RNA interference (RNAi) causes regeneration o

210 Initially, both wnt1 and notum (Wnt inhibitor) are expressed in all wounds, but 4