sonic hedgehog influences on skeletal muscle

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Research article BMC Developmental Biology 2004, 4:9

Hedgehog can drive terminal differentiation of amniote slow skeletal

muscle

Xaiopeng Li , S Blagden , Heidi Bildsoe , Marie-Ange Bonnin ,

Delphine Duprez and Simon M

Published

6 July 2004

Abstract

Background

Secreted Hedgehog (Hh) signalling molecules have profound influences on

many developing and regenerating tissues. Yet in most vertebrate tissues

it is unclear which

Hh-responses are the direct result of Hh action on a particular cell

type because Hhs frequently elicit secondary signals. In developing

skeletal muscle, Hhs promote slow myogenesis in zebrafish and are

involved in specification of medial muscle cells in amniote somites.

However, the extent to which non-myogenic cells, myoblasts or

differentiating myocytes are direct or indirect targets of Hh signalling

is not known.

Results: We show that Sonic hedgehog (Shh) can act directly on cultured

C2 myoblasts,

driving Gli1 expression, myogenin up-regulation and terminal

differentiation, even in the presence of growth factors that normally

prevent differentiation. Distinct myoblasts respond differently to Shh:

in some slow myosin expression is increased,

whereas in others Shh simply enhances terminal differentiation. Exposure

of chick wing bud cells to Shh in culture increases numbers of both

muscle and non-muscle cells, yet simultaneously enhances differentiation

of myoblasts. The small proportion of differentiated muscle cells

expressing definitive slow myosin can be doubled by Shh. Shh

over-expression in chick limb bud reduces muscle mass at early

developmental

stages while inducing ectopic slow muscle fibre formation. Abundant

later-differentiating fibres, however, do not express extra slow myosin.

Conversely, Hh loss of function in the limb bud, caused by implanting

hybridoma cells expressing a

functionally blocking anti-Hh antibody, reduces early slow muscle

formation and

differentiation, but does not prevent later slow myogenesis. Analysis of

Hh knockout mice indicates that Shh promotes early somitic slow

myogenesis.

Conclusion: Taken together, the data show that Hh can have direct

pro-differentiative

effects on myoblasts and that early-developing muscle requires Hh for

normal differentiation and slow myosin expression. We propose a simple

model of how direct and indirect effects of Hh regulate early limb

myogenesis.