Myostatin, a member of the TGF-␤ family, has been identified as a powerful inhibitor of muscle growth. Absence or blockade of myostatin induces massive skeletal muscle hypertrophy that is widely attributed to proliferation of the population of muscle fiber-associated satellite cells that have been identified as the principle source of new muscle tissue during growth and regeneration. Postnatal blockade of myostatin has been proposed as a basis for therapeutic strategies to combat muscle loss in genetic and acquired myopathies. But this approach, according to the accepted mechanism, would raise the threat of premature exhaustion of the pool of satellite cells and eventual failure of muscle regeneration. Here, we show that hypertrophy in the absence of myostatin involves little or no input from satellite cells. Hypertrophic fibers contain no more myonuclei or satellite cells and myostatin had no significant effect on satellite cell proliferation in vitro, while expression of myostatin receptors dropped to the limits of detectability in postnatal satellite cells. Moreover, hypertrophy of dystrophic muscle arising from myostatin blockade was achieved without any apparent enhancement of contribution of myonuclei from satellite cells. These findings contradict the accepted model of myostatin-based control of size of postnatal muscle and reorient fundamental investigations away from the mechanisms that control satellite cell proliferation and toward those that increase myonuclear domain, by modulating synthesis and turnover of structural muscle fiber proteins. It predicts too that any benefits of myostatin blockade in chronic myopathies are unlikely to impose any extra stress on the satellite cells. muscle growth ͉ muscular dystrophy ͉ TGF-beta ͉ muscle stem cells ͉ myonuclear domain L oss of muscle mass and strength is a major clinical feature of inherited myopathies such as Duchenne muscular dystrophy (DMD) and also of more common acquired atrophies associated with disuse, aging, and cancer. This loss has fostered widespread interest in the powerful inhibitory effect of myostatin, a member of the TGF-␤ family of signaling molecules, on muscle growth (1) with specific focus on the prospect of modulating this system to counteract atrophic processes. Indeed, muscle fiber hypertrophy arising from absence or blockade of myostatin has been reported to be associated with therapeutic benefits in the mdx mouse model of DMD (2, 3). This hypertrophy has been attributed to proliferation of satellite cells (4, 5), the principal cellular source for growing and regenerating skeletal muscle (6-10), consequent upon their release from myostatin inhibition (5,11,12).Here, we have investigated the contribution of satellite cells in 2 myostatin-null mouse models, constitutive (mstn Ϫ/Ϫ ) and compact (BEH c/c ), and following myostatin blockade by AAVmediated overexpression of myostatin propeptide. These data, together with our results from in vitro studies on the effect of presence or absence of myostatin on satellite cells contradict co...

BackgroundThe capacity of muscle to grow or to regenerate after damage is provided by adult stem cells, so called satellite cells, which are located under the basement lamina of each myofiber. Upon activation satellite cells enter the cell cycle, proliferate and differentiate into myoblasts, which fuse to injured myofibers or form new fibers. These processes are tightly controlled by many growth factors.ResultsHere we investigate the role of bone morphogenetic proteins (BMPs) during satellite cell differentiation. Unlike the myogenic C2C12 cell line, primary satellite cells do not differentiate into osteoblasts upon BMP signaling. Instead BMP signaling inhibits myogenic differentiation of primary satellite cells ex vivo. In contrast, inhibition of BMP signaling results in cell cycle exit, followed by enhanced myoblast differentiation and myotube formation. Using an in vivo trauma model we demonstrate that satellite cells respond to BMP signals during the regeneration process. Interestingly, we found the BMP inhibitor Chordin upregulated in primary satellite cell cultures and in regenerating muscles. In both systems Chordin expression follows that of Myogenin, a marker for cells committed to differentiation.ConclusionOur data indicate that BMP signaling plays a critical role in balancing proliferation and differentiation of activated satellite cells and their descendants. Initially, BMP signals maintain satellite cells descendants in a proliferating state thereby expanding cell numbers. After cells are committed to differentiate they upregulate the expression of the BMP inhibitor Chordin thereby supporting terminal differentiation and myotube formation in a negative feedback mechanism.

The layered organization of the cerebral cortex develops in an inside-out pattern, a process which is controlled by the secreted protein reelin. Here we report on cortical lamination in the Gli3 hypomorphic mouse mutant Xt(J)/Pdn which lacks the cortical hem, a major source of reelin(+) Cajal Retzius cells in the cerebral cortex. Unlike other previously described mouse mutants with hem defects, cortical lamination is disturbed in Xt(J)/Pdn animals. Surprisingly, these layering defects occur in the presence of reelin(+) cells which are probably derived from an expanded Dbx1(+) progenitor pool in the mutant. However, while these reelin(+) neurons and also Calretinin(+) cells are initially evenly distributed over the cortical surface they form clusters later during development suggesting a novel role for Gli3 in maintaining the proper arrangement of these cells in the marginal zone. Moreover, the radial glial network is disturbed in the regions of these clusters. In addition, the differentiation of subplate cells is affected which serve as a framework for developing a properly laminated cortex.

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