0

&

. : 2014-2015

jimlignos@gmail.com

kleanthisrdoct@gmail.com

Copyright 2015

mailto:jimlignos@gmail.commailto:kleanthisrdoct@gmail.com

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

us

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

us

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

us

27

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

28

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

us

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

us

34

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

us

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

us

37

Hoxa5 Cdx2/4

Hoxb8.

Hox Cdx.

Hox

-

, . -

Cdx2/4 Hoxa5 Hoxb8 -

, 39

Hox, ,

Hox -

.

Nucle

us

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

us

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 -