Six1 regulates proliferation of Pax7+ muscle progenitors in zebrafish

Abstract

SummaryIn the embryonic zebrafish, skeletal muscle fibres are formed from muscle progenitors in the paraxial mesoderm. The embryonic myotome is mostly constituted of fast-twitch-specific fibres, which are formed from a fast-specific progenitor cell pool. The most lateral fraction of the fast domain in the myotome of zebrafish embryos derives from the Pax7-positive dermomyotome-like cells. In this study, we show that two genes, belonging to the sine oculus class 1 (six1) genes (six1a and six1b), are both essential for the regulation of Pax7 + cell proliferation and, consequently, in their differentiation during the establishment of the zebrafish dermomyotome. In both six1a and six1b morphant embryos, Pax7 + cells are initially formed but fail to proliferate, as detected by reduced levels of the proliferation marker phosphohistone3 and reduced brdU incorporation. In congruence, overexpression of six1a or six1b leads to increased Pax7 + cell number and reduced or alternatively delayed fibre cell differentiation. Bone morphogenetic protein signalling has previously been suggested to inhibit differentiation of Pax7 + cells in the dermomyotome. Here we show that the remaining Pax7 + cells in six1a and six1b morphant embryos also have significantly reduced pSmad1/5/8 levels and propose that this leads to a reduced proliferative activity, which may result in a premature differentiation of Pax7 + cells in the zebrafish dermomyotome. In summary, we show a mechanism for Six1a and Six1b in establishing the Pax7 + cell derived part of the fast muscle and suggest new important roles for Six1 in the regulation of the Pax7 + muscle cell population through pSmad1/5/8 signalling.

MicroRNA-30a regulates zebrafish myogenesis via targeting the transcription factor Six1

“…2C, red arrows), and that the overall cross-sectional diameter was decreased (Fig. 2D, inset), which is consistent with what has been previously reported using a splice-blocking six1a MO (Nord et al, 2013). In addition, loss of the ability to refract polarized light (birefringence) demonstrated that six1a knockdown led to irregular muscle fiber arrangement (Fig.…”

“…During early myogenesis, knockdown of mouse and zebrafish Six1 results in severe muscle hypoplasia and a decrease in fast-twitch fibers (Bessarab et al, 2008;Grifone et al, 2005;Laclef et al, 2003a;Nord et al, 2013), demonstrating a role for Six1 in both muscle progenitor activation and the promotion of fast muscle differentiation. However, overexpression of Six1 in zebrafish also prevents fast twitch fiber formation (Nord et al, 2013), indicating that improper Six1 levels, either too high or low, can negatively affect early muscle differentiation. To date, mechanisms controlling Six1 expression during embryogenesis have not been elucidated in any tissue.…”

“…six1a and six1b are both required for proper primary myogenesis Previously, six1b was characterized as a transcription factor important for fast muscle myogenesis in zebrafish (Bessarab et al, 2004;Bessarab et al, 2008;Nord et al, 2013), whereas six1a had not been extensively studied in muscle development. However, six1a was recently shown to promote proliferation of fast muscle progenitors (Nord et al, 2013).…”

“…However, six1a was recently shown to promote proliferation of fast muscle progenitors (Nord et al, 2013). Because six1a has three binding sites for miR30a in its in 39UTR, we first examined the broader contribution of six1a to early myogenesis.…”

SIX1 is overexpressed in endometrial carcinoma and promotes the malignant behavior of cancer cells through ERK and AKT signaling

“…SIX1 expression level is increased in embryogenesis and promotes progenitor cell expansion and survival (6)(7)(8). SIX1 absence results in the reduction in size or loss of numerous organs, as a result of inhibited proliferation and increased apoptosis in mice (9).…”