Notch :

Notch

1. Notch

2. Notch

Notch NICD

3. Notch Notch

4. Notch Notch

Notch

5. Notch - - , , Notch - Notch

3o

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1. Notch

Notch , . otch , . otch , . , otch , "" .

, , notch .

otch 90 Drosophila (notch = ) , (Dexter, 1914). otch Drosophila Poulson (1937), o Notch , . 1985, Notch (Warton et al, 1985).

3.1 . (delta) otch . otch, , otch ( delta) .

Notch-like :

Caenorhabditis elegans ( LIN-12 GLP-1), , (Notch 1-4).

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otch 300 kDa . otch , -.

36 - EGF (epidermal growth factor) 3 (LNR). RAM , CSL . (TAD: transcriptional activator domain), otch (nls: nuclear localization sequences) PEST ( , , , ), (. 3.2).

3.2 Notch. otch 36

EGF 3 (LNR). otch RAM, 6 , TAD (transcriptional activator domain), nls (nuclear localization sequences) PEST ( , , , ).

, Notch

otch , O-- (O-Fut), Golgi. Golgi furin-like -Fut, 1 , (, Fringe) . ( ).

Notch 3 . . 3 (Itch, NEDD4, Su(dx) Deltex), Notch Notch , , . tch , GTP Rab. Notch ( ).

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,

Notch

3.3 ,

Notch. otch , O-- (O-Fut), Golgi. Golgi furin-like -Fut (, Fringe) . ( 3 ) Noptch 3 (Itch, NEDD4, Su(dx) Deltex), , , , . Sarah Bray, Notch signaling: a simple pathway becomes complex, Molecular Cell Biology, 2006, 7, 678-689.

2.

otch. ( ) otch Drosophila , Delta

Serrate, Caenorhabditis Lag-2 Delta 1 2 Jagged 1 2. DSL Ligand (Delta-Serrate-LAG). .

3.4 Notch Delta , . , Notch .

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(effector) otch Suppressor f Hairless [Su(H)] Drosophila, CBF Lag-1o Caenorhabditis. CSL effector (CBF-Su(H)-Lag). [E(spl)], HES.

Notch

DSL ligand Notch Receptor CSL effector Caenorhabditis elegans

Drosophila melanogaster

Vertebrates

Lag-2, -1, ARG-1, DSL1

Delta, Serrate Delta1-4, Serrate, Jagged 1,2

LIN-12, GLP-1

Notch

Notch 1-4

LAG-1

[Su(H)]

CBF1/RBPJ

Drosophila

: otch . , Notch Su(H). Su(H) E(spl) , HES, Helix-Loop-Helix (. 3.5). S , .

bHLH

Su(H)

3.5 otch , Notch (CD) Su(H), HES, Helix-Loop-Helix (bHLH). S 2.

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Notch -

otch, ( Delta-Serrate-Lag).

otch/ EGF otch EGF .

3.6 Notch Delta Serrate,

Drosophila. Blair Seth, Notch signaling: Fringe really is a glycosyltransferase, Current Biology, 2002, 10: R608-R612.

: . cis , otch . , Golgi, , . , - Delta Serrate, ( . ) ( . otch).

, Notch (.. CADASIL, Alagille), .

: Neuralized (Neur) Mind bomb (Mib), Notch, , , . Neur Mib , . Neur Drosophila . :

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3.8 Notch . Notch, NICD (Notch intracellular domain) . Kimble J., et al, Notch/LIN-12 signaling: transduction by regulated protein slicing, Trends in Biol. Sci., 1998, 23, 353-357.

,

, - .

3.7 . 3 Neuralized (Neur) Mind bomb (Mib) Notch. Neur Mib, . Neur ib Epsin- . Sarah Bray, Notch signaling: a simple pathway becomes complex, Molecular Cell Biology, 2006, 7, 678-689.

Notch

Notch , . (DSL). Notch, otch . Notch, .

Ntch

To otch

Delta/Notch

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Notch , S1, S2, S3. S1

Golgi furin-like . , . otch .

S2 . , ADAM-10 Kuzbanian ADAM-17 TACE (TNF--converting enzyme), S1 , Notch, . Notch NEXT.

S3 , -, ( 1-2), Pen2, Aph1 . S3 otch NICD (tch intracellular domain), . NICD , DNA , NLS (nuclear localization signal). S3 Notch, S3 .

-: ADAM -

Furin-like

-

3.9 otch. otch , Golgi, (TMIC

ECN) (S1 ). , otch , ADAM-10 ADAM-17 (S2 ), NEXT. S3 , , -, ( 1-2), Pen2, Aph1 . otch NICD, . Mumm J.S. and Kopan R. Notch signaling, From the outside in, Devel. Biol., 2000, 228, 151-165.

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3.10 Notch .

, otch , ADAM-10 CE (S2 ). S3 , -,. otch, Nicd, . Sarah Bray, Notch signaling: a simple pathway becomes complex, Molecular Cell Biology, 2006, 7, 678-689.

NICD

NICD, NLS (nuclear localizing signals) . , DNA, CSL (CBF1, Su(H) Lag1), , -, . - , SMRT, SHARP ( MINT S) CtBP, Drosophila Hairless, CtBP Groucho (Gro). SKIP (Ski-interacting protein). - (DACs), . COREPRESSOR COMPLEX .

NICD CSL, SMRT CSL. ( ) SKIP, NICD, , NICD SMRT. NICD, , SMRT CSL. NICD-CSL RAM NICD. , -, HDACs Mastermind HATs (pCAF, GCN5). HATs-NICD-SKIP-CSL (INTERMEDIATE COMPLEX) , . HATs INT.COMPLEX SMRT CSL, NICD. , - 8 (CDK8) 3 SEL10 Nicd, .

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CSL:

(CBF1, Su(H), Lag1)

-

,

HDACs:

HAs: ,

3.11 otch , -. Sarah Bray, Notch signaling: a simple pathway becomes complex, Molecular Cell Biology, 2006, 7, 678-689.

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3. Ntch

Notch . otch , . , , , . (NICD) , , , .

( ), NICD, , . , 3 NICD. NICD, , , . Notch ( 3.12). , -, 3 .

3.12 .

, 1 (ubiquitin-activating ), 2 (ubiquitin-conjugating ). , 3 (), (NICD). , . : Lubert Stryer et al., Biochemistry.

3 NICD ( Sel 10, Itch, suppressor of deltex) tch (eur, Mind bomb) Notch (LNX). 3 ( HECT, F-box RING), ( Itch 3 , Sel 10 ) ( 3.13).

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1. Sel 10 Sel 10 Caenorhabditis elegans, Notch. , F-box WD-40. F-box , PEST NICD, . NICD.

2. Suppressor of deltex Itch: Notch Suppressor of deltex Drosophila melanogaster. , Deltex ( Notch). , Suppressor of deltex WW NICD, . Notch. Suppressor of deltex, , Itch. . Itch JNK1.

3. LNX LNX 3 Numb, . Numb Notch, . LNX Notch, Numb.

3.13 , 3 , Notch. - - (NICD) 3 . : Eric C. Lai, Current Biology, 2002, 12, R74-R78.

3.14 Drosophila. () Drosophila, , () , Suppressor of Deltex. Bernd J., and Preiss A., Mechanisms of Development, 2002, 115, 3-14.

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4. euralized euralized (neur) Drosophila, , , . NHR (neuralized homology repeat) RING (Really Interesting New Genes), 3 . eur Notch, , . , NICD, , Notch, .

Notch Notch Fringe. , Scabrous, .

Notch EGF, . - (-Fut) 1 . -Fut Notch. O-Fut , - Notch . -Fut , Notch .

1 , . Fringe.

3.15 3 Notch. sel-10 NICD. Su(dx)/Itch: suppressor of deltex Itch NICD, . eur Notch, , . LNX Numb, Notch. : Eric C. Lai, Current Biology, 2002, 12, R74-R78.

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1. Fringe Fringe Drosophila (fringe=) , . -, trans-Golgi - EGF-like 22 36 Notch, trans-Golgi. tch , Fringe Notch : , Fringe Notch Serrate, ( Delta). Fringe (boundary formation), , Drosophila. , Drosophila, , ( 3.16).

Fringe Serrate Delta . , Fringe otch Serrate, . , Notch . , , Fringe otch, Delta . . Serrate . Delta . 3.16 () Drosophila.

(dorsal) , (ventral) (margin) . () Drosophila: Fringe Drsophila , .

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Boundary formation 3.17 , .

() Notch Delta , Notch Serrate , . , Serrate Fringe, Notch . : M.Baron et al., Molecular Membrane Biology, 2002, 19, 27-38. () Fringe Serrate , Delta , Notch . Fringe. : Seth S. Blair, Current Biology, 2000, 10, R608-R612.

2. Scabrous

Scabrus Notch, . Notch. Scabrous Notch (SOPs). Scabrous, Notch, . , , Scabrous, Notch , ( : lateral inhibition).

Lateral inhibition

Scabrus Notch Fringe, Notch .

3.18 Scabrous SOPs Notch signaling SOPs, Scabrous, Notch (). , Scabrous, () Notch .

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3.19 NOTCH (a) otch S1

Golgi. otch Delta. Notch Delta. , 3 neuralized. (b) S2 ADAM Kuzbanian. (c) S3 Notch -, . NIC . (d) , NIC Su(H)/CBF1, NIC , , NIC , . (e) NIC sel-10, . (f) otch , 3 , Su(dx)/Itch. (g) notch cis- notch, . (h, i) Kuzbanian Neuralized: (h) Kuzbanian (i) euralized , cis- otch. Baron ., Seminars in Cell & Developmental Biology, 2003, 14, 113-119

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Notch

otch . - , Notch ..., , , , , Drosophila .

notch . ( ) . Notch ; - otch, , .

4. Notch

Notch , Notch 1.

Notch

otch 9 , , IC Notch . , o Tanigaki et al (2001) , Notch ( 2).

, Notch , CSL DNA HES (Hairy/Enhancer of Split genes), MASH . , MASH , . , () MASH, . , , . 1 : , . . . 2 : , . , . . 2 : , , .

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3.20 otch (NICD) , . , (Ngn) . Lundkvist J. and Lendahl U., Notch and the birth of glial cells, Trends in Neurochem. Sci., 2001, 24, 492-494.

Notch

(cortical ventricular zone, VZ) . , .19, . , , P9 , P21.

, , (radial glia), (VZ) ( 3.18 3.19). Notch . , . , . , . Notch, , .

, Notch - , .

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3.22 (VZ) , . : . (), . : Eric R.Kandel et al. .

3.21 . . ) (EARLY), . (stem cell) Notch, (radial glia), (cortical plate). ) (LATE), , notch , Notch signaling , . : Nicholas J.Justice Yuh Nung Jan, Current opinion in Neurobiology, 2002.

. .

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5. Notch - - , ,

. O (, , , , , ). :

, .

, .

( ), , . , .

-

- Notch ,

, ( 3.20).

Notch

Notch

Notch

Notch

Notch

3.23 Notch, .

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Notch

Notch , , - Notch. Notch-1 (NICD) ( CD4+, CD8+) - , , -. , Notch-1 , - CD44+, CD25-, CD4-, CD8-) - .

, Notch-1 -, - .

Notch -

Notch, , , .

( , , , ), (, , ) , .

( ) ( 3.21). 90% , . .

3.24 ) . ) . ( , , , ), . () , .

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- . , (CD45RO, CD45RA, CD3, CD2, TCR), - ( 3.22).

3.25 . TCR: ( ), -. CD4: - . CD8: - . Roitt et al., , . 18, 2000.

(DN1, DN2, DN3, DN4,

DP) (SP). DN1, -, -

. , . DN2-4 - (TCR: T cell receptor). , TcR. - , -. , TcR ( 1% - TCR). TcR , TcR . - -. , .

3.26 TcR(-

) - (MHC, Classe I/II). ,,, - CD4/8, MHC.

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DP, ( 99% -) CD4 CD8. , . , , TcR, CD4 CD8 MHC- . MHC- . ,

(CD4 CD8) . , TcR//MHC-. , cR , , MHC-, CD4 (- ). , TcR MHC-, CD8 (- ).

3.27 - (H helper) - (C cytotoxic) .

Notch

- , - - , CD4+ CD8+ .

Notch-1+/- TcR- Notch-1+/+, Notch TcR . , -TcR Notch-1 -, TcR Notch-1, -.

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Notch TcR- CD8+ CD4+. , Notch, (- CD4+ - CD8+). Notch -.

3.28

Notch . : Izon Dj, Punt JA, Pear WS Deciphering the role of Notch Signalling in Lymphopoiesis, Current Opinion Immunology, 2002, 14:192-1999.

Notch

Notch , Lunatic Fringe, Deltex Numb.

Lunatic Fringe EGF (Epidermal Growth Factor)-like Notch, Serrate. , Notch , . , Notch (Delta 1, 2 Jagged 1, 2).

TCR+ Notch 1+

TCR+CD4+ CD8-

TCR+CD4- CD8+

DP

DP

- -

Notch 1+

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Deltex Notch, CSL. CSL- Notch.

Numb , Notch. , Numb Notch . , Lunatic Fringe, Deltex Numb .

3.29 Notch , Lunatic Fringe, Deltex Numb. : Izon Dj, et al. Deltex1 directs lymphoid progenitors to B cell lineage by antagonizing Notch1, Immunity, 2002, 16: 231-243, ..

3.30 Notch Lunatic Fringe, Deltex Numb.

, Notch, . , , Notch .

-Fringe, -Numb

-Deltex Notch

+ Fringe + Numb

+ Deltex Notch

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Artavanis-Tsakonas S. et al, Notch signaling: cell fate control and signal integration in

development, Science, 1999, 284, 770-776 Baker NE., Notch signaling in the nervous system. Pieces still missing for puzzle, Bioessays,

2000, 22, 264-73 Baron ., An overview of the Notch signaling pathway, Seminars in Cell & Developmental

Biology, 2003, 14, 113-119 Baron ., H. Aslam, M. Flasza, M. Fostier, J.E. Higgs, S.L. Mazaleyrat and M.B.Wilkin,

Multiple level of Notch signal regulation, Molecular Membrane Biology, 2002, 19:27-38

Bernd J., and Preiss A., Wing vein formation in Drosophila melanogaster: Hairlaiss is involved in the cross-talk between Notch and Egf signaling pathways, Mechanisms of Development, 2002, 115, 3-14

Blair Seth, Notch signaling: Fringe really is a glycosyltransferase, Current Biology, 2002, 10: R608-R612

Bray S., A Notch affair, Cell, 1998, 93, 499-503 Deftos Michael, Michael J Bevan, Notch signaling in T cell development, Current opinion in

immunology, 2000, 12: 166-172. Frisen J. and Lendahl U., Oh no, Notch again, Bioessays, 2001, 23, 3-7 Guidos Cynthia J, Notch signaling in lymphocyte development, Immunology, 2002, 14: 395-

404. Izon Dj, et al., Deltex1 directs lymphoid progenitors to B cell lineage by antagonizing

Notch1, Immunity, 2002, 16: 231-243. Izon Dj, Punt JA, Pear WS, Deciphering the role of Notch Signaling in Lymphopoiesis,

Current opinion in Immunology, 2002, 14:192-199. Joutel A. and Tournier-Lasserve E., Notch signaling pathway and human diseases, Cell &

Dev. Biol., 1998, 9, 619-25 Justice Nicholas and Yuh Nung Jan: Variations on the Notch pathway in neuronal

development, Current pinion in Neurobiology, 2002, 12:64-70 Haltiwanger Robert and Pamela Stanley, Modulation of receptor signaling by glycosylation:

fringe is an O-fucose-1,3-N-acetylglucosaminyltransferase, Biochimica et Biophysica Acta, 2002, 1573: 328-335

Hansson EM., Lendahl U., Chapman G., Notch signaling in development and disease, Seminars in Cancer Biology, 2004, 14, 320-328

Kandel Eric, James H. Schwartz and Thomas M. Jessell, , E , 1999

Kojika S. and Griffin D., Notch receptors and hematopoiesis, Exp. Hematology, 2001, 29, 1049-1052

Kimble J., Henderson S., and Crittenden S., Notch/LIN-12 signaling: transduction by regulated protein slicing, Trends in Biol. Sci.,1998, 23, 353-357

Lai E., Protein Degradation: Four E3s for the Notch pathway, Current Biology, 2002, 12: R74-R78

Lai E., Notch signaling: control of cell communication and cell fate, Development, 2004, 131, 995-973

Lundkvist J. and Lendahl U., Notch and the birth of glial cells, TiNS, 2001, 24, 492-494 Louvi A., Artavanis-Tsakonas, Notch signaling in vertebrate neural development, Nature

Reviews in Neurosciences, 2006, 7, 93-102 Mumm J.S. and Kopan R. Notch signaling, from the outside in, Devel. Biol., 2000, 228, 151-

165

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Pires-daSilva A., Sommer RJ., The evolution of signalling pathways in animal development, Nat Rev Genet, 2003, 4, 39-49

Roitt, Brostoff, Male, , , 2000, 2: 14-20, 12: 158-159.

Vander, M.D; Sherman Ph.D; Luciano, Ph. D; M. ,Tsakopoulos, , .. , 2001.

Weinmaster G., Notch signal transduction: a real rip and more, Curr. Opin. Genet. Dev.,2000, Yeh Edward, Matt Dermer and Cosimo Commisso, Lily Zhou, C. Jane McGlade and

Gabrielle L.Boulianne, Neuralized functions as an E3 ubiquitin ligase during Drosophila development, Current Biology, 2001, 11:1675-1679

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