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0
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. : 2014-2015
Copyright 2015
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Nucle
us
1
.. . 2
. . 3
.. . 8
Hox:
Drosophila Hox . 8
Droshophila . 13
Hox . 18
HOX . 23
O . . 29
Cdx Hox -
. . 34
homeobox
Cdx2 -
.. . 38
Ellis-van Creveld (EVS) MSX1 .. . 41
.. . 45
......................... . 46
-
Nucle
us
2
H -
. -
-
/ /
( ).
-
.
. -
-
-
(.. HOX 1, 2).
-
. DNA
-
() . 180 -
. () (homeodo-
main) ( ) DNA. H
-
DNA.
,
. -
. K ,
homeodomain
. -
-
. -
Droshophila ().
-
Nucle
us
3
. -
, , ,
.
,
()
.
; -
, -
,
( ) .
.
, -
.
( ) ,
-
-
Hox. -
-
-
( -
)
.
-
-
-
.
: Drosophila (), Droshophila - antennapedia (). : (), - (Bottom images courte-sy of the Archives, California Institute of Technology http://learn.genetics.utah.edu/content/variation/hoxgenes/
-
Nucle
us
4
; -
,
DNA . -
,
(homeobox) Hox.
180 -
.
-
homeoboxes , -
, .
Hox .
-
. ,
.
. -
homeobox DNA , -
-
.
-
-
-
.
, , -
, .
-
Nucle
us
5
-
Hox,
homeo-
boxes,
-
.
,
, -
-
, -
.
-
.
, -
-
,
-
4
Hox. 600
7. -
, Hox . , Hox - . (Illustraiton based on information from Pascual-Anaya et al (2005), Carroll et al (2005), and Garcia-Fernandez (2013). http://learn.genetics.utah.edu/content/variation/hoxgenes/)
-
Nucle
us
6
.
, , (3) -
.
, ( -
).
, -
. ,
.
-
Hox. 40 Hox, -
(A, B, C D), -
.
, Hox
.
, -
-
-
-
-
.
-
. -
Hox . (: http://learn.genetics.utah.edu/content/variation/hoxgenes/)
-
Nucle
us
7
, . -
, , ,
.
Hox ,
,
.
-
Nucle
us
8
Hox: Dro-sophila Hox
.
.
-
. Hox
, Drosophila. -
,
-
.
.
Drosophila
melanogaster, (homeosis).
Hox ;
. , Hox
(.. -
, , ),
.
. , Hox /
-
.
Hox . ( Exd Hth,
Pbx Meis ). , Hox
Exd. -
-
Hox -
. , Hox -
. ,
-
Nucle
us
9
Keilin .
, Hox
. ,
Hox -
.
Drosophila,
,
Drosophila. () 16 H165-lacZ - () -odd () -Prc (). H165 (CM). 7981 Odd Prc o (PC) , Odd (LG) -. , . (B) 16 H15-lacZ -- () -Svp Dorsal (). CMs . Svp . ( 12 CMs, - svp) ( 2 Svp+ 4 Svp- ). (C) 16 - -Ubx (), -AbdA () -Tin () . Ubx CMs ( ) PCs ( ) , abdA CMs PCs . CMs . (D) - . (D D) (D) (D) , - . (E) - Hox . . (: Bruno Monier et al, 2007, Downstream of Homeotic Genes: In the Heart of Hox Function. Fly 1:2, 59-67)
-
Nucle
us
10
. -
-
.
, / , -
, -
. , , -
, ,
, -
, 52 .
, , -
.
Hox.
Hox : An-
tennapedia (Antp), Ultrabithorax (Ubx), Abdominal-A (abdA) Abdominal-B (abdB).
[ : Labial, Proboscipedia, Deformed Sex combs re-
duced (Scr), .]
Hox -
. -
, -
( ) ( ) .
Ubx abdA
. -
; ,
.
, abdA -
E,
Ubx. , E
, ,
. , Ubx abdA
-
Nucle
us
11
Seven-up (Svp).
. Hedgehog (Hh) -
. , -
Ubx abdA -
.
Antp . -
, ,
svp.
Antp svp, -
svp .
-
,
,
. Ubx abdA -
, abdA
Ubx . ,
abdA ,
.
-
, Ubx -
abdA, -
Ubx
AbdA.
Hox.
Drosophila
. Hox -
:
,
-
-
Nucle
us
12
. -
,
,
Hox .
-
. 104
: ,
.
- . -
.
-
Hox.
-
Nucle
us
13
- Droshophila
-
(hindbrain) .
() -
Droshophila
. /
(anteroposterior), -
Droshophila
.
-
.
Droshophila
.
Droshophila 8 2 -
, :
Antennapedia
Bithorax
E -
-
.
-
. -
Bi-
thorax .
.
-
Nucle
us
14
(HOX) 4 ( -
:
.
.)
.
Hox -
-
-
-
-
.
-
-
-
,
-
-
-
() -
.
. :
Labial
Deformed
o : labial (lab), proboscipedia (pb), Deformed (Dfd), Sex combs reduced (Scr), Antennapedia (Antp), Ultrahithorax (Uhx), ab-dominal-A (abd-A) Abdominal-B (abd-B) 14 HRP. - . (: Frank Hirth, Beate Hartmann & Heinrich Reichert, 1998, Homeotic gene action in embryonic brain development of Droshophila). Available online at: http://dev.biologists.org/content/125/9/1579.short)
-
Nucle
us
15
-
. ,
( ) o , -
.
Droshophila
:
1)
2) (ventral nerve cord-VNC)
- -
. -
- . - ,
.
-
.
5 Antennapedia -
.
.
1. lab :
-
2. pb ,
pb
15-20 .
3. Dfd
.
4. Scr -
-
-
Nucle
us
16
5. To ntp
6. Bithorax
.
7. Ubx -
2 neuromere 7 -
3 / A1 .
8. Abd- 1 -
7 .
9. , '''' -
11/12 . ,
Abd-B
14. , Abd-B
: (mandibular-S1), (maxillary-S2), (labial-S3) (Vental nerve cord-VNC). Droshophila 14 . HoxB 9.5-12 . HoxB; Droshophila . HoxB - . (: Frank Hirth, Beate Hartmann & Heinrich Reichert, 1998, Homeotic gene action in embryonic brain development of Droshophila) Available online at: http://dev.biologists.org/content/125/9/1579.short)
-
Nucle
us
17
7
, 5
.
( .
. ) 5
:
1) lab, 2) pb, 3) Dfd, 4) Scr 4) Antp
Bithorax . -
Ubx, abd-A, Abd-B.
-
Nucle
us
18
Hox
, .
, -
, , -
. ,
.
-
, .
,
. , -
. In vivo,
, p53, -
, , , homeoboxes, Hox .
Hox 39 ,
1-13 .
, Hox
, HOX.
. ,
in vivo in vitro .
Hox -
,
Hox in vivo in vitro .
, .
Hox
-
in vitro in vivo,
.
(MSCs),
.
-
Nucle
us
19
(ESCs)
.
Hox -
. Hox -
. , Hox -
.
-
(HSCs)
-
-
. -
-
-
,
-
.
-
. ,
Hoxa , HOXB4
.
(NCCs) -
. -
, -
. NCCs
- HOX. (: http://atlasgeneticsoncology.org/)
-
Nucle
us
20
.
NCCs -
.
, ,
.
, ,
, , . Hox
NCCs. , Hoxa2 Hoxd9
, . , Hoxd3
-
(MSCs)
MSCs , in vitro -
, -
, -
, , , , .
, , , -
. MSCs
, , .
-
. Hox
, Hox -
-
Hox.
MSCs (CB-MSC) -
(USSCs) . CB-MSCs
HOXA9, HOXB7, HOXC10 HOXD6, USSCs -
ESCs Hox . CB-MSCs USSCs -
-
: CB-MSCs
USSCs -
. HOXB7 HOXD6
MSCs MSCs -
. MSCs
-
Nucle
us
21
HOXC10. ,
HOXA5 10, HOXB6, 7, HOXC4, C6, C8, C9 C10, HOXD3 D8 -
MSCs . MSCs
Hoxb2, 5, 7 Hoxc4, -
.
(CSCs) , -
,
-
.
-
-
,
-
. -
. ,
CSCs
. -
,
CSCs. DNA
CSCs
. , -
,
, . -
Hox
, -
Hox -
. CSCs () - , CSCs (), - , (: Ricardo Pardal et al, 2003, Applying the principles of stem-cell biology to cancer Nature Reviews Cancer 3, 895-902)
-
Nucle
us
22
. , HOXA9 -
. HOXB7, HOXC6 C9 -
-
, -
. , HOXA4
HOXD10 .
Induced Pluripotent Stem Cells (iPS)
(iPS) ESCs
.
,
Hox. iPS -
. ,
, , ,
-, ,
-. iPS
ESCs,
Hox .
.
-
- Hox Hox
HSC HOXA
HOXB4 MSC HOXA5, 10
Hox -
HOXB6, 7
HOXC4, 6, 8, 9, 10
HOXD3 D8 ESC Hox
CSC Hox -
HOXA9 HOXB7, C6, C8 HOXA4, D10
NCC HOXD3
iPS Hox
-
Nucle
us
23
HOX
Hox
, ,
, -
. , -
, II ,
. , -
, .
-
33-L1 , Hoxa4, 7, Hoxd4 -
. -
(hAT-SC), HOXC8
. , ,
RNA, -
miRNAs. HOXC8 hAT-SC -
, Hox -
.
HOXA1, 4 HOXC4 -
( ) -
. , Hox
. -
in vitro -
. ,
Hox
.
Hox - -
, . , -
-
.
, ,
. -
, .
-
Nucle
us
24
-
. Hox
, in vitro in vivo,
,
Hoxa2 Hoxd9 .
Hox ,
. -
Hox , -
, .
, Hox - -
.
Hoxc8 Hoxd4 -
. Hoxc8 , -
, -
, -
. Hoxa11 Hoxd11. D
Hox
(MSCs) . -
Hox
in vivo in vitro.
Hox -
, -
50% .
,
,
.
in vivo in vitro. MSCs -
, -
-
, .., ,
. -
Hox
-
Nucle
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25
MSCs
.
HOXA1 ,
, -
. TCDD (2,3,7,8-Tetrachlorodibenzo-p-dioxin) -
-
. Hoxa10, 13, 7, Hoxb9, Hoxc8,
C9, Hoxd1, 4, D9, D13 Hoxb1 .
, Hoxa10 in vivo
.
, HOXA11 13 ,
MyoD -
Hox.
Hox
MSCs ex vivo.
Hox6-10
(SMCs) - SMCs
- , , . -
(ESCs) -
, ,
Hox -
ESCs. (VW-
MPSCs) HOXB7, HOXC6 C8 -
ESCs,
.
Hox VW-MPSCs
(Matrigel),
. , , Hox
.
Hox -
. ESCs ,
Hoxa3 Hoxd3, -
, .
,
-
Nucle
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26
Hoxa5 Hoxd10 -
. ,
Hox
. Hoxa5 Hoxd10 ESCs
, Hoxa3 Hoxd3
/ . -
Hoxd10 ,
Hoxd3 Hoxb3 .
Hox ESCs
,
.
, HOXA9, 13, HOXB2, 3, 4, 5, 6 -
. , HOXA9
,
Hox
.
Hox. 5 BMP Wnt. Hox 3 , , . (: Anne Seifert et al, 2015, Role of Hox genes in stem cell differentiation, World J Stem Cells 2015 April 26; 7(3): 583-595)
-
Nucle
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MSCs
Hox
. HOXA7 HOXB3 , HOXA3
HOXB13 . , HOXB5 -2
, -
. , HOXB5
-
. Hox
, -
-
.
Hox -
. -
, . -
. Hox - () ,
3 Hox -
1-4 .
(RA) -2 (RALDH2) (-: Thomas J. Cunningham et al, 2015, Mechanisms of retinoic acid signalling and its roles in organ and limb development, Nature Reviews Molecular Cell Biology 16, 110123)
-
Nucle
us
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5-13
. AP
.
, Hoxb1
,
, -
, . Hoxa2 Hoxb1 -
, .
Hoxb1, .
, HOXB4 -
. ,
Hoxa1 ,
Hox . (RA),
.
-
Hox. Hox
(RAREs),
RA- ESCs. RAREs Hoxa1, a4,
Hoxb1, b4, Hoxd4. , Hox
RA. -
, Hox
,
Hox. ,
Hox
.
-
Nucle
us
29
O
.
,
-
- 4
: HOXA, HOXB, HOXC HOXD 2, 7, 12
17 .
-
-
. -
.
.
-
. -
-
, , -
-
. -
18 24 .
.
-
, . -
. -
.
.
-
Nucle
us
30
,
-
.
-
.
(FGF- Fibroblast growth factors), (TGF-
transforming growth factors), Wnt (Wingless) -
Shh (Sonic hedgehog). T -
.
:
, / , -
,
-
.
-
/ .
.
-
( : -
, -
housekeeping genes) / -
.
H -
.
-
Nucle
us
31
.
.
(Hypodontia): 5 -
(Oligodontia): 6
.
(Anodontia): -
.
.
8
, /.
MSX1, PAX9, AXIN2,EDA DLX.
-
.
(, , ) , . .
-
Nucle
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32
1) MSX-1 (Muscle segment homeobox containing
transcription factors).
( Ellis-van
Creveld MSX-1) -
4p16.1. ( 4
16.1.). -
a 297.
.
-
.
MSX-1 -
.
2) PAX (Paired Box)
14q12-14q13
.
.
3) AXIN2 (Axin Inhibition Protein 2)
-
( -
).
(/). -
-
-
.
4) EDA1
- (Ectodysplasin-A/EDA)
EDA. -
-
.1 ( -
-
Nucle
us
33
) -
EDA .
5) DLX
.
. -
-
.
-
-
. -
,
, -
. ,
. ,
-
, -
-
.
____________________
1 : http://ghr.nlm.nih.gov/condition/hypohidrotic-ectodermal-dysplasia
http://ghr.nlm.nih.gov/condition/hypohidrotic-ectodermal-dysplasia -
Nucle
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Cdx Hox
Cdx Hox
.
Cdx -
. -
Hox.
, -
. , -
Cdx Hox -
(Wnt signaling).
Hox ParaHox -
ProtoHox . Hox
-
. , ProtoHox
. Cad (Caudal-
related gene) Cdx. -
ProtoHox
ParaHox Cdx2
Cdx ,
Cdx1 Cdx4.
Hox -
, -
, ,
. Hox, Cdx
, -
.
-
Nucle
us
35
-
Cdx1 Cdx4 -
. , -
Cdx2 -
, -
.
Cdx2
. Cdx2
Cdx4 (Cdx2+/-/Cdx4-/-) -
.
Cdx2+/-/Cdx4-/- ( -
Cdx2/4) -
. ,
10,5 -
(10,5) -
,
-
-
Cdx. Cdx2/4
9,5 -
.
Cdx . (A B) (A) (WT) Cdx2/4 (B) E9.0. - . (C-E) - 15.5. (F-M) In situ . (H-M) 10.5 WT Cdx2/4. (H I) Mesp2,. (J ) Hes7, (L M) Uncx4.1. (C) - () (F) - (). 0.25mmin () (), 1.5mmin (C) - (), 0.5mmin (F) - (). (: Teddy Young et al, 2009, Cdx and Hox Genes Differen-tially Regulate: Posterior Axial Growth in Mammalian Embry-os Developmental Cell 17, 516526, Elsevier Inc
-
Nucle
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36
15,5
. - -
Cdx2/4 , -
.
Cdx,
Cdx2
.
Cdx2/4 -
, -
(PSM) -
.
Cdx Hox
-
, Hox
. Cdx Hox,
Hoxa5 Hoxb8. Hox
Cdx.
Hoxb8 Hoxa5, Cdx
, -
Cdx2/4
. Hox. -
Cdx2 -
Cdx2 -
. Hox
Cdx2
. Cdx2Hoxa5 Cdx2Hoxb8 -
. Cdx2/4, Hoxb8
Cdx2
.
Cdx2/4 ,
Cdx2/4 Hoxb8 .
-
Nucle
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Hoxa5 Cdx2/4
Hoxb8.
Hox Cdx.
Hox
-
, . -
Cdx2/4 Hoxa5 Hoxb8 -
, 39
Hox, ,
Hox -
.
-
Nucle
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38
homeobox Cdx2
Cdx2 , -
-
. , -
,
,
.
Hox -
, -
. -
-
.
-
APC, K-Ras, p53 Bcl2, -
.
homeobox Cdx2, Drosophila, -
. ,
Cdx2 (Cdx2-/-) . -
8,5 , .
,
.
knock-out Cdx2,
(Cdx2+/-) ,
-
. ,
,
.
Cdx2
.
-
Nucle
us
39
, Cdx2
. , , -
Cdx2 . -
,
Cdx2 -
.
Cdx2 -
(Cdx2+/-) . , , -
-
.
, -
azoxymethane (AOM),
. ,
. -
() Cdx2+/- . () - ( ) Cdx+/- , 12 , ( ) () . () ( & ) (ad) - (ca) . (C) (sm). - (D) () . 67 - (F) (G) . - (H) (). , - (J), - (), () , (). * - . 200 mm (, C), 50 mm (D-I), 20 mm (J, K). (: C Bonhomme et al, 2003, The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development, Gut 2003;52:14651471)
-
Nucle
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40
AOM .
Cdx2
.
Cdx2 , -
(Cdx2+/-)
.
.
, Cdx2
. DNA
Cdx2+/- AOM PCR
,
Cdx2. , -
-
.
, Cdx2+/-
.
Cdx2
, .
,
. , Cdx2 -
AOM . ,
Cdx2 -
.
, APC p53,
, Cdx2 -
-
-. ,
.
-
Nucle
us
41
Ellis-van Creveld (EVS) MSX1
. To Ellis - van Creveld -
(). , -
.
(),
. -
,
-
. -
-
.
To Ellis van
Creveld
4p16.1.
MSX1 (homeobox gene- -
DNA
180 .. homeodomain)
4p16.1. To Msx
, -
.
Droshophila 1984 -
, ,
.
DNA -
. HOX A, B, C
Ellis-van Creveld. : (Courtesy of David Rimoin, Cedars-Sinai Medical Center, Los An-geles, California.)
-
Nucle
us
42
D 4 -
. .
Droshophila.
-
-
180 .. -
-
-
-
.
Msx -
-
Droshophila -
.
-
Msx -
-
EVC -
, (hypodontia, natal teeth).
-
msx1 EVC;
msx-1 -
, -
Amish, llis-van Creveld. . (: Courte-sy of the Alan Mason Chesney Medical Archives)
-
Nucle
us
43
.
(4p16.1.)
:
1)
2) .
MSX1 2 -
1.6 kb. -
297 .
453 .. 438 ..
MSX1 2 ( ) . . (Available online at:
http://jdr.sagepub.com/content/87/2/119.full.pdf+html)
EVC
PCR -
http://jdr.sagepub.com/content/87/2/119.full.pdf+html -
Nucle
us
44
5 . 5 2
EVC 2 . -
PCR
.
. -
(direct sequencing) -
(fluorogram) 2
.
-
-
, , -
.
, Msx1
( -
EVC) -
EVC -
.
MSX1 Ellis-van Creveld
. -
/
.
-
Nucle
us
45
-
. HOX,
,
. 39 -
(A-D) , 7p15, 17q21.2,
12q13 2q31
. ,
-- , -
HOXA13 HOXD13. -
Hox . -
MLL,
trithorax Drosophila, -
-
. MLL -
, , ,
.
-
, -
.
.
MLL -
. ,
HOX,
. -
.
-
Nucle
us
46
1. About phenotype of Ellis-van Creveld syndrome:
http://ghr.nlm.nih.gov/condition/ellis-van-creveld-syndrome
2. Anne Seifert, David F Werheid, Silvana M Knapp, Edda Tobiasch, 2015, Role of Hox
genes in stem cell differentiation, World J Stem Cells; 7(3): 583-595
3. Bruno Monier, Florencia Tevy, Laurent Perrin, Maria Capovilla & Michel Semeriva, 2007,
Downstream of Homeotic Genes: In the Heart of Hox function, Fly 1:2, 59-67
4. C Bonhomme, I Duluc, E Martin, K Chawengsaksophak, M-P Chenard, M Kedinger, F
Beck, J-N Freund, C Domon-Dell, 2003, The Cdx2 homeobox gene has a tumour sup-
pressor function in the distal colon in addition to a homeotic role during gut develop-
ment, Gut; 52:14651471
5. Frank Hirth, Beate Hartmann and Heinrich Reichert, 1998, Homeotic gene action in
embryonic brain development of Drosophila, Development 125, 1579-1589
6. Josef G. Heuer, Thomas C. Kaufman, 1992, Homeotic genes have specific functional
roles in the establishment of the Drosophila embryonic peripheral nervous system, De-
velopment 115, 35-47
7. R.L.Nussbaum, R.R.McInnes, H.F.Willard, 2011, Thompson & Thompson -
, 2 , ...
8. Sreevalli Suryadeva, Mohammadi BegumKHan, 2015, Role of Homeobox Genes in
Tooth Morphogenesis: A Review, Journal of Clinical and Diagnostic Research. Vol-9(2):
ZE09-ZE12
9. Susan E. Ide Rosa Isela Ortiz De Luna, Clair A. Francomano Mihael H. Polymeropou-
los, 1996, Exclusion of the MSX1 homeobox gene as the gene for the Ellis van Creveld
syndrome in the Amish, Hum Genet 98 : 572575
10. Teddy Young, Jennifer Elizabeth Rowland, Cesca van de Ven, Monika Bialecka, Ana
Novoa, Marta Carapuco, Johan van Nes, Wim de Graaff, Isabelle Duluc, Jean-Noe l
Freund, Felix Beck, Moises Mallo, Jacqueline Deschamps, 2009, Cdx and Hox Genes
Differentially Regulate Posterior Axial Growth in Mammalian Embryos, Developmental
Cell 17, 516526
11. Terence RJ Lappin, David G Grier, Alexander Thompson, Henry L Halliday, 2006, HOX
GENES: Seductive Science, Mysterious Mechanisms, Ulster Med J.; 75(1): 2331.
12. University of Utah Health Sciences, Learn.Genetics, Homeotic Genes and Body Patterns
http://learn.genetics.utah.edu/content/variation/hoxgenes/
http://ghr.nlm.nih.gov/condition/ellis-van-creveld-syndromehttp://learn.genetics.utah.edu/content/variation/hoxgenes/ & Hox: Drosophila Hox Droshophila Hox HOX O Cdx Hox homeobox Cdx2 Ellis-van Creveld (EVS) MSX1 -