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Development 2014 Apr 01;1417:1503-13. doi: 10.1242/dev.101436.
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Sub-circuits of a gene regulatory network control a developmental epithelial-mesenchymal transition.

Saunders LR , McClay DR .

Epithelial-mesenchymal transition (EMT) is a fundamental cell state change that transforms epithelial to mesenchymal cells during embryonic development, adult tissue repair and cancer metastasis. EMT includes a complex series of intermediate cell state changes including remodeling of the basement membrane, apical constriction, epithelial de-adhesion, directed motility, loss of apical-basal polarity, and acquisition of mesenchymal adhesion and polarity. Transcriptional regulatory state changes must ultimately coordinate the timing and execution of these cell biological processes. A well-characterized gene regulatory network (GRN) in the sea urchin embryo was used to identify the transcription factors that control five distinct cell changes during EMT. Single transcription factors were perturbed and the consequences followed with in vivo time-lapse imaging or immunostaining assays. The data show that five different sub-circuits of the GRN control five distinct cell biological activities, each part of the complex EMT process. Thirteen transcription factors (TFs) expressed specifically in pre-EMT cells were required for EMT. Three TFs highest in the GRN specified and activated EMT (alx1, ets1, tbr) and the 10 TFs downstream of those (tel, erg, hex, tgif, snail, twist, foxn2/3, dri, foxb, foxo) were also required for EMT. No single TF functioned in all five sub-circuits, indicating that there is no EMT master regulator. Instead, the resulting sub-circuit topologies suggest EMT requires multiple simultaneous regulatory mechanisms: forward cascades, parallel inputs and positive-feedback lock downs. The interconnected and overlapping nature of the sub-circuits provides one explanation for the seamless orchestration by the embryo of cell state changes leading to successful EMT.

PubMed ID: 24598159
PMC ID: PMC3957374
Article link: Development
Grant support: [+]

Genes referenced: alx1 arid3a erg ets1 etv6 foxb1 foxn3 foxo1 LOC100887844 LOC115919910 LOC575170 LOC753325 slc22a13 snai2 tbr1 tgif2l
Morpholinos: arid3a MO6 arid3a MO7 erg MO2 erg MO4 etv6 MO2 etv6 MO3 foxb1 MO1 foxb1 MO2 foxo1 MO1 foxo1 MO2 hhex MO2 hhex MO3 tgif2l MO2 tgif2l MO3

References [+] :
Acloque, Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease. 2009, Pubmed