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The Life of a Skeletal Muscle. Specification. Morphogenesis. Growth. Diseases. Genes Exogenous or Autonomous ? . Cell shape changes, migration - Identify positional cues. Stem cell origin -Proliferation Fusion. Genes Therapies. MyoD. S I. Initiation de la myogenèse. D.

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slide1

The Life of a Skeletal Muscle

Specification

Morphogenesis

Growth

Diseases

  • Genes
  • Exogenous or Autonomous ?
  • Cell shape changes,
  • migration
  • - Identify positional cues
  • Stem cell origin
  • -Proliferation
  • Fusion
  • Genes
  • Therapies
slide2

MyoD

S I

Initiation de la myogenèse.

D

dermomyotome

myotome

sclerotome

Neural tube

medial lip

sclerotome

epithelial

somite

slide3

Initiation de la myogenèse:

modèle inductif

  • Arguments expérimentaux:
  • Micromanipulations chez le poulet : rotation de somites > myogenèse normale
  • Culture de PSM souris et poulet:
  • + rien > rien
  • + Wnt > un peu
  • + Wnt + SHH > beaucoup

Wnt-6

Wnt-1

-3a, -4

MyoD

SHH

slide4

WT

Shh-/-

Smo-/-

Mais:

Myogenèse normale sans signal Hh

Myf5

E9.5

Zhang et al. 2001 Cell 105: 781-792

slide5

George-Weinstein M, Gerhart J, Reed R, Flynn J, Callihan B, Mattiacci M,

Miehle C, Foti G, Lash JW, Weintraub H.Skeletal myogenesis: the preferred

Pathway of chick embryo epiblast cells in vitro.Dev Biol. 1996

Jan 10;173(1):279-91.

Induction de la myogenèse: modèle permissif?

slide6

Les gènes de détermination myogénique

Famille des bHLH

Myogenic determination

MyoD

Myf5

Muscle differentiation

Myogenin

MRF4

Tous ont la capacité d’induire la myogenèse de cellules non myogéniques (gènes « maîtres »)

MyoD -/- et Myf5 -/- sont viables et fertiles

MyoD:Myf5 -/- létal, pas de muscle

Myogenin -/- et MRF4 -/- possèdent des myoblastes Myf5 ou MyoD-positifs,

mais la différenciation ultérieure est arrêtée.

MyoD/Myf5: gènes de spécification

Myogenin/MRF4: gènes de différentiation

slide7

Et avant les gènes de détermination

myogénique?

Poulet 3 jours, section transversale, anticorps anti Pax3. Remarquer les cellules

migrant dans le mésenchyme de l’aile.

Pax3 et Pax7, exprimés de manière similaire (TN et somites ou muscles)

slide8

Skeletal muscles are ablated in the body of Sp/Myf5 double homozygous embryos

Tajbakhsh et al., 1996 Cell 89: 127-138

Pax3: rôle au cours de la migration des progéniteurs musculaires (membres)

Collaboration de Myf5 et Pax3 pour la myogenèse des muscles du corps

slide9

Alveolar Rhabdomyosarcomas

  • Pediatric solid tumors of skeletal muscle in Human.
  • Chromosomal translocation t(2;13)(q35;q14) PAX3-FKHR

PD

L

HD

1

479

PAX3 (PAX7) (weak transactivation/repression)

655

1

FKHR

AD

FH

1

837

PAX3-FKHR (strong transactivation)

(PAX7-FKHR)

AD

PD

L

HD

slide10

Muscle satellite cells in Pax7 mutant mice

Pax7: phénotype chez l’adulte cellules souches (satellites) apoptotiques

Pax3 : Pax 7 -/- pas de progéniteurs musculaires

slide11

Early muscle morphogenesis

Pax-7

MHC

Dermomyotome

Myotome

slide12

The Electroporation Technique

Lineage studies

- GFP reporter

Functional Studies

- GOF

- LOF (DN molecules, siRNAs)

+

-

E 2.5

slide13

MEDIAL

LATERAL

POSTERIEUR

ANTERIEUR

NT

slide14

ANTERIOR

POSTERIOR

MEDIAL

LATERAL

NT

NT

NT

NT

48h

slide15

E 4.5

The formation of the myotome

Medial

Caudal

+

Rostral

Lateral

slide16

Questions

-Primary myotome morphogenesis:

-organized cellular movements

-positional information

-Mechanisms regulating muscle growth:

-Origin of muscle stem cells?

-Proliferation and differentiation (common mechanisms

in the embryo & adult)?

slide17

Origine embryonnaire des cellules souches

du muscle squelettique de l’adulte

Cellules satellites: Somites?

Aorte dorsale?

Moelle osseuse?

Sat. C.

SP

Cellules « SP »

slide18

Cellules souches du muscle squelettique

de l’adulte: cellules satellites

5-12/fibre

slide19

+24h

mGFP / Ncadh

+12h

My

+36h

+48h

mGFP / Ncadh

Dermis ?

Phalloidin / F-actin staining

The EMT of the dermomyotome …

slide20

24 hours

… triggers the entry of a population of muscle

progenitors in the primary myotome...

36 hours

48 hours

Actin / GFP

slide25

Pax3-/-; Pax7-/-:

NO progenitors

Partie centrale

bordures

EMT

Myotome primaire

(MyHC, MyoD, Myf5)

slide28

Regulation of the fusion of muscle cells

?

Descriptive analysis of fusion in the chick embryo:

When does fusion start?

Determine which cell types fuse?

2. Identify chick homologs of Drosophila genes, perform ISH

3. Functional analyses in the chick (GOF, LOF).

In progress…