Segregation of striated and smooth muscle lineages by a Notch-dependent regulatory network

Abstract

BackgroundLineage segregation from multipotent epithelia is a central theme in development and in adult stem cell plasticity. Previously, we demonstrated that striated and smooth muscle cells share a common progenitor within their epithelium of origin, the lateral domain of the somite-derived dermomyotome. However, what controls the segregation of these muscle subtypes remains unknown. We use this in vivo bifurcation of fates as an experimental model to uncover the underlying mechanisms of lineage diversification from bipotent progenitors.ResultsUsing the strength of spatio-temporally controlled gene missexpression in avian embryos, we report that Notch harbors distinct pro-smooth muscle activities depending on the duration of the signal; short periods prevent striated muscle development and extended periods, through Snail1, promote cell emigration from the dermomyotome towards a smooth muscle fate. Furthermore, we define a Muscle Regulatory Network, consisting of Id2, Id3, FoxC2 and Snail1, which acts in concert to promote smooth muscle by antagonizing the pro-myogenic activities of Myf5 and Pax7, which induce striated muscle fate. Notch and BMP closely regulate the network and reciprocally reinforce each other’s signal. In turn, components of the network strengthen Notch signaling, while Pax7 silences this signaling. These feedbacks augment the robustness and flexibility of the network regulating muscle subtype segregation.ConclusionsOur results demarcate the details of the Muscle Regulatory Network, underlying the segregation of muscle sublineages from the lateral dermomyotome, and exhibit how factors within the network promote the smooth muscle at the expense of the striated muscle fate. This network acts as an exemplar demonstrating how lineage segregation occurs within epithelial primordia by integrating inputs from competing factors.

MicroRNA MiR-199a-5p Regulates Smooth Muscle Cell Proliferation and Morphology by Targeting WNT2 Signaling Pathway

“…Id3 is an important regulator of gene expression, playing a critical role in SM differentiation (32,57). Id3 has been shown to inhibit striated muscle differentiation, preventing myoblast-myotube conversion (58) by antagonizing the promyogenic activities of Myf5 and Pax7 (32). Up-regulation of Id3 observed here offers an additional argument supporting the importance of miR199a-5p in dystrophic muscle.…”

“…Here we report an increase of Id3 mRNA and protein levels in miR-199a-5p-overexpressing SMCs. Id3 is an important regulator of gene expression, playing a critical role in SM differentiation (32,57). Id3 has been shown to inhibit striated muscle differentiation, preventing myoblast-myotube conversion (58) by antagonizing the promyogenic activities of Myf5 and Pax7 (32).…”

“…Id3 is an important regulator of smooth muscle differentiation program (32). It is localized in the nucleus of bladder SMCs (Fig.…”

γ‐Secretase Inhibition Induces Muscle Hypertrophy in a Notch‐Independent Mechanism

“…Our data shows that chick muscle cells have at least two different sizes of Notch‐1 fragments. Our results showing the expression of Notch in cultures of chick muscle is in accordance with the data presented by Applebaum and colleagues, which described the expression of Notch in the dermomyotome of chick embryos.…”

Segregation of striated and smooth muscle lineages by a Notch-dependent regulatory network

“…Antibodies used were against GFP (1:500; Invitrogen, Life Technologies, Grand Island, NY, USA), quail endothelial marker Qh1 (1:10) and Pax7 (1:10) (both from Developmental Studies Hybridoma Bank, University of Iowa, Iowa City, IA, USA), desmin (1:100; MP Biomedicals, Santa Ana, California, USA) and SMA (1:200; Sigma-Aldrich, Rehovot, Israel), both recognizing smooth and striated muscle [65], and ZO-1 (1:100, Zymed, Life Technologies, Grand Island, NY, USA). Secondary antibodies were coupled either to Cy2 or Rhodamine (1:100; Jackson ImmunoResearch Laboratories, West Grove, PA, USA).…”