ライフサイエンスコーパス: reelin

1 tical circuits by secreting the glycoprotein reelin.

2 abrogated the decrease in VLDLRs induced by Reelin.

3 roteolytic processing of endothelium-derived Reelin.

4 mation was the extracellular matrix molecule reelin.

5 rogliaform subtype, express the glycoprotein Reelin.

6 egulated by the extracellular matrix protein Reelin.

7 man astrocyte cell culture model to identify reelin, a factor intimately involved in the development

8 Initial studies found that loss of Reelin, a large, secreted glycoprotein encoded by the Re

9 sticity and NMDA receptor phosphorylation by Reelin, a regulator of brain development and modulator o

10 n the marginal zone, and their expression of reelin, a signal that controls spatial ordering of corti

11 cortices that lack the secreted glycoprotein Reelin, a subset of neurons completed migration but then

12 Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of

13 report that the extracellular matrix protein Reelin, acting through its downstream, intracellular Dab

14 The specificity of Reelin action on spontaneous neurotransmitter release is

15 We propose a multistep mechanism in which Reelin activates Rap1, Rap1 upregulates NCad, and NCad i

16 ed in cortical interneurons: Reln coding for reelin; Adamts8 and Adamts15 belonging to the class of m

17 of CLASP2 regulates its interaction with the Reelin adaptor Dab1 and this association is required for

18 Reelin affects multiple pathways including through the r

19 Here, we show that Reelin also acts presynaptically, resulting in robust ra

20 Here, we identify Reelin, an extracellular matrix glycoprotein previously

21 Reelin, an extracellular matrix molecule, regulates neur

22 els of the extracellular matrix glycoprotein Reelin and activation of its downstream pathway resultin

23 Using reelin and apoE as ligands, we studied the impact of VLD

24 l in which activation of VLDLR and apoER2 by reelin and apoE induces ABCA1 expression and cholesterol

25 In addition, both reelin and apoE3 significantly increased phosphorylated

26 Reelin and apolipoprotein E (apoE), ligands of apoE rece

27 In vivo, Reelin and Dab1 are required for the normal extension of

28 bind to extracellular glycoproteins, such as Reelin and F-spondin, which leads to phosphorylation of

29 Furthermore, induction of the reelin and GAD67 mRNAs is accompanied by the dissociatio

30 nd striatal demethylation of hypermethylated reelin and GAD67 promoters.

31 thylation of GABAergic gene promoters (i.e., reelin and GAD67).

32 The FAK-Src complex, activated by upstream reelin and integrin beta1, can initiate a cascade of pho

33 -R2 and N-R6 bind to L1 and that full-length Reelin and its N-terminal fragment N-R6 proteolytically

34 Here, we report that full-length Reelin and its N-terminal fragments N-R2 and N-R6 bind t

35 We also show that Reelin and LGI1 co-localize in a subset of rat brain neu

36 inguished by the combinatorial expression of Reelin and Slit1.

37 At E15.5, expression of reelin and VLDLR was similar but expression of apolipopr

38 SPNs in reeler (which lacks reelin), and in mice deficient in components of the reel

39 We propose a model in which Abeta, Reelin, and ApoE receptors modulate neurotransmission an

40 cts of normal and reeler mutant mice lacking Reelin, and from cell-free extracts containing normal or

41 entral spinal cord; the only areas devoid of Reelin are areas occupied by SPN or somatic motor neuron

42 hanisms that mediate postnatal activities of Reelin are not well understood.

43 We identified the glycoprotein reelin as a potentially useful marker, because it is exp

44 e that the direct interaction between L1 and Reelin as well as the Reelin-mediated generation of L1-8

45 2, a dual function receptor for ApoE and for Reelin, as well as NMDA and AMPA receptors by sequestrat

46 s pathway could be used as murine models for Reelin-associated vocal deficits in humans.

47 ate that LXR activation results in decreased Reelin binding to VLDLR and reduced Dab1 phosphorylation

48 Extracellular Reelin binds to cell surface receptors and activates pho

49 estration of extracellular reelin with CR-50 reelin-blocking antibodies suppressed the increase in mi

50 5-beta bound to specific promoter regions of reelin, brain-derived neurotrophic factor (BDNF), and gl

51 y the dimeric ligands Fc-RAP, F-spondin, and Reelin but relatively weak clustering with the ligand ap

52 Dab1 is required for most effects of Reelin, but Dab1-independent pathways may contribute.

53 containing the extracellular matrix protein Reelin, but not control medium, further increased the ve

54 hatic endothelial cells in turn responded to Reelin by up-regulating monocyte chemotactic protein 1 (

55 At high concentrations of Abeta peptides, Reelin can no longer overcome the Abeta induced function

56 Here we show that Reelin can prevent the suppression of long-term potentia

57 oreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential im

58 Activation of the Reelin cascade leads to phosphorylation of Disabled-1, a

59 Deficiency in Reelin causes the forming dendrite to avoid its normal t

60 Reelin choreographs neuronal migration to establish lami

61 we identified Dgcr2 as a novel member of the Reelin complex, regulating the phosphorylation of Reelin

62 Kdm5b depletion increased extracellular reelin concentration in the culture medium and increased

63 ndrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 wit

64 not clear whether the secreted glycoprotein Reelin controls migration and dendritic growth as relate

65 Reelin controls neuronal positioning in the developing b

66 However, little is known about how Reelin controls the cytoskeleton during neuronal migrati

67 Reelin coordinates the movements of neurons during brain

68 Furthermore, loss of Reelin correlates with decreased survival of lung and br

69 Our findings suggest that reelin could be a previously unknown factor involved in

70 This demonstrates that the balance between Reelin-Dab1 signaling and LKB1-Stk25-GM130 regulates Gol

71 nclusively demonstrate an important role for Reelin-Dab1 signaling in the adult forebrain, and unders

72 ful to study the biological functions of the Reelin-Dab1 signaling pathway both in vitro and in vivo.

73 The Reelin-Dab1 signaling pathway regulates development of t

74 We find that Stk25, a modifier of Reelin-Dab1 signaling, regulates Golgi morphology and ne

75 Knock-out of APP or Reelin decreased dendritic arborization in cortical neur

76 In contrast, Reelin decreased VLDLRs, which was accompanied by an inc

77 xamine the cytoarchitectural consequences of Reelin deficiency, using high-throughput histology and n

78 rigin of cognitive disorders associated with Reelin deficiency.

79 Reelin-deficient (Reeler) mice exhibited impaired respon

80 We found that Reelin-deficient mice have reduced levels of the cleaved

81 Reelin-deficient mice showed abnormal collecting lymphat

82 , albeit less severe than, those observed in Reelin-deficient or VLDLR/ ApoER2 double-KO mice.

83 ficient mice partially overlap with those of Reelin-deficient reeler mice.

84 Therefore, this study links Reelin-dependent dendritogenesis with migration arrest a

85 s of early corticogenesis possibly through a Reelin-dependent mechanism.

86 is coincides with a complete blockade of the Reelin-dependent phosphorylation of NR2 subunits.

87 n complex, regulating the phosphorylation of Reelin-dependent substrates and the expression of Reelin

88 n-dependent substrates and the expression of Reelin-dependent transcriptional targets.

89 f SPN through electroporation of full-length Reelin DNA stopped SPN migration toward their destinatio

90 Induction of the Reelin/E-cadherin axis is also observed in Kras mutant l

91 our data reveal that CLASP2 is an essential Reelin effector orchestrating cytoskeleton dynamics duri

92 gulates cell movement, and both X11alpha and Reelin enhance this effect.

93 are fundamental to the proper integration of Reelin-expressing interneurons into nascent cortical cir

94 early development, superficially positioned Reelin-expressing neurogliaform interneurons in the mous

95 By measuring reelin expression and promoter methylation status in 39

96 Here we analyzed reelin expression by immunohistochemistry in 17 normal b

97 developing DG, perhaps in part by affecting Reelin expression in a key compartment directly above th

98 dorsomedial cortex, and ventral expansion of Reelin expression in the cortical plate of the frontal c

99 ack toward the central canal, despite strong reelin expression in the ventricular zone.

100 of heterozygous reeler mice (HRM), in which reelin expression is down-regulated by approximately 50%

101 er decitabine treatment, we established that reelin expression levels correlated inversely with promo

102 The spatiotemporal pattern of Reelin expression, along with the inhibition of SPN migr

103 is a marked decrease ( approximately 50%) of reelin expression.

104 sition can change with location and level of reelin expression.

105 sed neurite outgrowth in vitro and prevented Reelin from increasing neurite outgrowth.

106 Thus, we define the cellular mechanism of reelin function during radial migration, elucidate the m

107 Loss of Reelin function results in the severe developmental diso

108 migration by exogenous Reelin, suggests that Reelin functions as a barrier to SPN migration during no

109 Therefore, Reelin functions as part of a polarity signaling system

110 APP and Reelin have previously been shown to promote neurite out

111 Reelin ibsVRG neurons were larger (27.1 +/- 3.8 mum in d

112 This finding suggests that lack of reelin impairs GABAergic Purkinje neuron expression and/

113 ity against the extracellular matrix protein Reelin in a region directly above the developing LSB is

114 n promoter, we examined here the function of Reelin in control of sympathetic preganglionic neurons (

115 R and Dab1, that mediates other functions of Reelin in early brain development.

116 hese phenotypes are suggestive of a role for reelin in spatial patterning or structural organization

117 However, unlike reeler, levels of reelin in the C3G(gt)/(gt) spinal cord are normal, and D

118 The present study examined the effects of Reelin in the migration of sympathetic preganglionic neu

119 Ectopic expression of Reelin in the pathway of SPN through electroporation of

120 uronal maturation and synaptic plasticity by Reelin in the postnatal and adult brain.

121 Only when the expression level of ectopic reelin in the ventricular zone became very weak (E18.5)

122 Reelin in turn mediates inhibitory signals to migrating

123 decreased migration in response to exogenous reelin in vitro, a response that required Dab1.

124 s, these observations 1) solidify a role for Reelin in vocal communication of multiple species, 2) po

125 Reelin increased cell surface levels of APP and decrease

126 These results show that Reelin-induced Akt stimulation and Dab1 turnover are not

127 trated that this subunit is not required for Reelin-induced Dab1 phosphorylation.

128 ha3beta1 integrin antibody prevented APP and Reelin-induced neurite outgrowth.

129 n contrast, two downstream signaling events, Reelin-induced phosphorylation of C3G and Akt, were not

130 Reelin-induced tyrosine phosphorylation is responsible f

131 Using coimmunoprecipitation, we found that Reelin interacted with APP through the central domain of

132 In the present study, we examined whether Reelin interacts with APP, and the functional consequenc

133 These findings demonstrate that Reelin interacts with APP, potentially having important

134 d aberrant neurogenesis with preservation of reelin + interneurons, lowered concentration of oxidativ

135 Reelin is a glycoprotein that is critical for proper lay

136 Reelin is a neuromodulator that increases glutamatergic

137 Reelin is a secreted, signaling protein associated with

138 We suggest that reelin is a useful molecular marker for pre-BotC neurons

139 Reelin is an extracellular matrix protein synthesized in

140 Reelin is an extracellular matrix protein that is vital

141 Reelin is an extracellular protein essential for neurona

142 Reelin is an extracellular protein that controls many as

143 The secreted glycoprotein Reelin is an important factor directing neuronal migrati

144 Reelin is essential for the stereotypical inside-out seq

145 Together, these data reveal that reelin is essential for the targeting of LGN subnuclei b

146 During secondary migration, abundant Reelin is found in large areas of the ventral spinal cor

147 Reelin is known to activate signalling cascades regulati

148 uggest that in the subventricular zone where Reelin is not present but ApoER2, VLDLR, and Dab1, clust

149 In vivo, Reelin levels were increased in brains of APP knock-out

150 The Reelin ligand regulates a Dab1-dependent signaling pathw

151 g of clusterin to these receptors triggers a Reelin-like signal in cells expressing disabled-1 (Dab1)

152 The regulation of VLDLR by BDNF and Reelin may affect the migration of neurons and contribut

153 We conclude that reelin may play an important role in controlling invasiv

154 n, which suggests an autocrine mechanism for Reelin-mediated control of endothelial factor expression

155 raction between L1 and Reelin as well as the Reelin-mediated generation of L1-80 contribute to brain

156 Reelin-mediated generation of L1-80 is involved in neuri

157 To address their specific roles in Reelin-mediated neuronal migration, we generated mutant

158 pectedly, we discovered that the full-length Reelin moiety, but not the central fragment, is capable

159 N markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (mu-opioid receptor 1), glutamate receptor

160 tion status, whereas demethylation increased reelin mRNA expression in vitro.

161 bserved between the two chemically identical reelin-N domains in one crystallographic asymmetric unit

162 Pre-BotC reelin neurons coexpress NK1R and Sst.

163 Reelin neurons were also found in the parahypoglossal an

164 in the developing cerebral cortex requires a Reelin-Notch interaction.

165 a critical role in mediating the effects of Reelin on neuronal cell migration.

166 Possible functions of Reelin on SPN migration are discussed.

167 Deletion in mouse of either reelin or Dab1 induced alterations in the development of

168 Treatment of these mouse macrophages with reelin or human apoE3 significantly increased ABCA1 mRNA

169 wborn progeny, is eliminated in mice lacking REELIN or upon clonal depletion of DISABLED-1, which com

170 derived cortical interneurons express either Reelin or vasoactive intestinal polypeptide.

171 calcium-binding protein 1, cholecystokinin, reelin, or a combination of these molecules.

172 Mice that are deficient in Dab1, Reelin, or the Reelin receptors ApoER2 and VLDLR exhibit

173 This reelin- or apoER2-mediated up-regulation of ABCA1 expres

174 Reelin overexpression in MDA-MB231 cells, as well as inc

175 ound mutants carrying mutations in both, the Reelin pathway and Lis1 exhibit hydrocephalus, a phenoty

176 We previously showed that the Reelin pathway and the Pafah1b complex interact genetica

177 Components of the Reelin pathway are highly expressed during development,

178 a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and t

179 nd loss-of-function studies to show that the Reelin pathway regulates migration and dendritic develop

180 t interacts with Dab1, a key mediator of the Reelin pathway that controls several aspects of brain de

181 isabled-1 is a key signaling molecule in the Reelin pathway that plays a critical role in neuronal mi

182 how that Dab1, an essential component of the reelin pathway, is required in radially migrating neuron

183 ent decrease in Dab1, a key component of the Reelin pathway, is sufficient to induce behavioral defic

184 Here we demonstrate that the Reelin pathway, which determines the development of laye

185 dent on Dab1, a key signaling protein in the Reelin pathway.

186 ted Dab1 to mediate downstream events in the Reelin pathway.

187 xon junction array search for Nova-dependent reelin-pathway RNAs at E14.5 revealed only one candidate

188 cule L1 and the extracellular matrix protein Reelin play crucial roles in the developing nervous syst

189 l striatum, are found in dopamine receiving, reelin-positive patches, and are born throughout striata

190 -cells in layer-2 emerged around birth while reelin-positive stellate-cells were scattered throughout

191 re caudally (>12.8 mm caudal to Bregma) than reelin pre-BotC neurons (15.5 +/- 2.4 mum in diameter, <

192 ls of histone H2B monoubiquitination, at the reelin promoter.

193 et out to express and purify the full length Reelin protein and a biologically active central fragmen

194 Loss of reelin protein expression correlated significantly with

195 Reelin protein is expressed in a complementary pattern,

196 Application of Reelin protein to reeler cortices destabilized tangentia

197 uction mechanisms elicited by these purified Reelin proteins in cortical neurons.

198 we demonstrate in mice that for CGE-derived reelin (Re)-positive and calretinin (Cr)-positive (but n

199 w here that BDNF increased the levels of the Reelin receptor (VLDL receptor (VLDLR)) in hippocampal n

200 catalytic subunit of Pafah1b also binds the Reelin receptor VLDLR.

201 of apolipoprotein E receptor 2 (ApoER2) (the reelin receptor) was much lower in LXRbeta(-/-) than in

202 Mice deficient in another Reelin receptor, very low-density lipoprotein receptor (

203 e that are deficient in Dab1, Reelin, or the Reelin receptors ApoER2 and VLDLR exhibit severely pertu

204 components of the reelin signaling pathway (reelin receptors VldlR and ApoER2, the cytoplasmic adapt

205 ITSN1 genetically interacts with Reelin receptors, as evidenced by the prominent neuronal

206 , triggers activation of this cohort of LRP8-Reelin-regulated neuronal (LRN) enhancers that serve as

207 bition and rescue experiments indicated that Reelin regulates migration through Rap1 and Akt, and tha

208 We discovered that Reelin regulates several phosphorylation sites within th

209 RGC axons in mutant mice lacking functional reelin (reln(rl/rl)) revealed reduced patterns of vLGN a

210 ession of the gene encoding the glycoprotein reelin (Reln) in Chd7-deficient GCps.

211 rt the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without L

212 We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerabili

213 We discovered a hypomorphic reelin (Reln) mutant with abnormal cortical lamination a

214 layering requires an extracellular protein, Reelin (Reln), an intracellular signaling molecule, Disa

215 dm5b depletion, notably the up-regulation of reelin (Reln), the inhibition of steroid biosynthetic pa

216 g glutamic acid decarboxylase 67 (GAD67) and reelin (RELN).

217 acted with APP through the central domain of Reelin (repeats 3-6) and the E1 extracellular domain of

218 This effect of Reelin requires a modest but significant increase in pre

219 ing downstream AKT signaling or inactivating reelin restored migration.

220 reeler mutant mouse, the lack of the protein Reelin results in cell-type and region-dependent changes

221 In contrast, intensity of reelin (RLN) expression was significantly increased in a

222 study on transgenic rl/rl mutants (rl/rl ne-reelin) shows that the initial migration of SPN (embryon

223 y for binding Disabled-1 and transducing the Reelin signal, was also necessary for development of the

224 euroblasts, which could be linked to reduced reelin signaling and disorganized radial glial cell fibe

225 on is spatiotemporally regulated to modulate Reelin signaling and ensure normal neuron positioning in

226 to highlight the most fundamental aspects of Reelin signaling and integrate how these various neuromo

227 f Dab1 to mediate neuronal responsiveness to reelin signaling and neuronal migration, suggesting new

228 er, it is not known whether a dysfunction in Reelin signaling during perinatal stages increases the r

229 ic mouse and retroviral reporters along with Reelin signaling gain-of-function and loss-of-function s

230 The interplay between BDNF and Reelin signaling in neurodevelopment is not fully unders

231 A recent paper uncovers a new function for Reelin signaling in specifying dendritic compartmentaliz

232 In the years since, the known functions of Reelin signaling in the brain have expanded to include m

233 These observations highlight a role for reelin signaling in the directed migration of mammary ep

234 increasing body of evidence to suggest that Reelin signaling is a critical player in the modulation

235 These results uncover a mechanism by which Reelin signaling is activated by communication between t

236 SIGNIFICANCE STATEMENT: Reelin signaling is important for brain development and

237 Reelin signaling is required for appropriate cell migrat

238 We find that Reelin signaling is required for the striking enrichment

239 fat pad and provide the first evidence that reelin signaling may be crucial for regulating the migra

240 , and in mice deficient in components of the reelin signaling pathway (reelin receptors VldlR and Apo

241 tify nectins and afadin as components of the reelin signaling pathway and demonstrate that coincidenc

242 The Reelin signaling pathway controls radial neuronal migrat

243 g cerebral cortex, but that mutations in the Reelin signaling pathway do not affect its expression.

244 er mice and subsequent identification of the Reelin signaling pathway have strongly informed models o

245 and suggest that C3G acts downstream in the reelin signaling pathway in control of SPN migration.

246 that binds CrkL, could act downstream in the reelin signaling pathway in control of SPN migration.

247 These findings suggest a central AKT-FOXG1-reelin signaling pathway in FMCD and support pathway inh

248 The Reelin signaling pathway plays a crucial role in regulat

249 ed dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprog

250 protein that is an obligate effector of the Reelin signaling pathway, and is critical for neuronal m

251 CLASP2 as a key cytoskeletal effector in the Reelin signaling pathway.

252 increased phosphorylation of the downstream reelin signaling target Disabled-1 (Dab1).

253 these data identify ITSN1 as a component of Reelin signaling that acts predominantly by facilitating

254 Furthermore, reelin signaling to Rap1 promotes neuronal Cdh2 function

255 lar adaptor protein activated in response to reelin signaling, is expressed in the developing mammary

256 Reelin signaling, which is mediated in part by a key ada

257 crease the risk of behavioral deficits alter Reelin signaling.

258 ons(SPNs) in the spinal cord is regulated by reelin signaling.

259 Disabled-1, an adaptor protein required for Reelin signaling.

260 n unexpected functional link between LXR and Reelin signaling.

261 and is involved in brain development through Reelin signaling.

262 s with phosphoDab1, an essential mediator of Reelin signaling.

263 nstream signaling adaptor Dab1 to facilitate Reelin signaling.

264 o psychiatric disorders linked to defects in Reelin signaling.

265 nes during memory formation, linking this to Reelin signaling.

266 gene encoding VLDLR, a receptor important in reelin signaling.

267 and epigenetic changes in components of the Reelin-signaling pathway (RELN, DAB1) are associated wit

268 multiple species, 2) point to the canonical Reelin-signaling pathway as critical for development of

269 uction or absence of these components of the Reelin-signaling pathway.

270 Reelin signals via the lipoprotein receptors very low de

271 Reelin simultaneously regulates NMDA-receptor transmissi

272 In reeler, which lacks Reelin, SPN also undergo primary migration to the ventro

273 Reelin stimulation of cultured neurons induces the exten

274 to defective neuronal migration and ablates Reelin stimulation of hippocampal long-term potentiation

275 tions significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on

276 the inhibition of SPN migration by exogenous Reelin, suggests that Reelin functions as a barrier to S

277 ells, as well as incubation with recombinant reelin, suppressed cell migration, invadopodia formation

278 Here we show that Reelin, the Rap1 GTPase and N-cadherin (NCad) are import

279 Reelin thus plays a role in restraining RAS and PI3-kina

280 , thereby critically reducing the ability of Reelin to enhance synaptic glutamate receptor activity.

281 In the neocortex, CR cells secrete reelin to instruct the radial migration of projection ne

282 The binding of Reelin to its receptor, LRP8, triggers activation of thi

283 As a result, the ability of Reelin to prevent LTP suppression by extracts from AD-af

284 e deacetylase inhibitors, partially restored reelin transcription and promoted the accumulation of mu

285 lls, due at least in part to derepression of reelin transcription in a manner dependent on the forkhe

286 Postnatally, SPN in rl/rl ne-reelin transgenic mice were located in both the IML and

287 Similarly, Reelin treatment increased cell velocity in the presence

288 multiple axons, both of which are rescued by Reelin treatment.

289 Using a transgenic mouse that expressed reelin under the nestin promoter, we examined here the f

290 Reelin was expressed in the luminal epithelium and myoep

291 ggregate near the central canal when ectopic reelin was expressed.

292 Recently, reelin was found to be epigenetically silenced in gastri

293 Although Reelin was identified more than a decade ago, its functi

294 sporter, GABA transaminase, parvalbumin, and reelin were all highly expressed in breast cancer metast

295 RELN encodes a secreted protein, Reelin, which has important functions in both the develo

296 Reelin, which is expressed in theca cells, triggers a si

297 g neural progenitors showed misexpression of reelin, which led to a non-cell autonomous migration def

298 lipoprotein receptor (Vldlr) and its ligand reelin, which unexpectedly regulate FGFR-dependent epith

299 However, the interaction of Reelin with adhesion molecules, such as L1, has remained

300 Sequestration of extracellular reelin with CR-50 reelin-blocking antibodies suppressed