Abstract
Ras-responsive element-binding protein 1 (Rreb1) is a zinc-finger transcription factor acting downstream of RAS signaling. Rreb1 has been implicated in cancer and Noonan-like RASopathies. However, little is known about its role in mammalian non-disease states. Here, we show that Rreb1 is essential for mouse embryonic development. Loss of Rreb1 led to a reduction in the expression of vasculogenic factors, cardiovascular defects, and embryonic lethality. During gastrulation, the absence of Rreb1 also resulted in the upregulation of cytoskeleton-associated genes, a change in the organization of F-ACTIN and adherens junctions within the pluripotent epiblast, and perturbed epithelial architecture. Moreover, Rreb1 mutant cells ectopically exited the epiblast epithelium through the underlying basement membrane, paralleling cell behaviors observed during metastasis. Thus, disentangling the function of Rreb1 in development should shed light on its role in cancer and other diseases involving loss of epithelial integrity.
Highlights
55 56 Ras-responsive element-binding protein 1 (RREB1) is a zinc-finger transcription factor that acts downstream of RAS (Thiagalingam et al, 1996)
Data were further validated by comparison to available single-cell transcriptomic datasets of equivalent embryonic stages (Figure 1 – figure supplement 1H) (Nowotschin et al, 2019; Pijuan-Sala et al, 2019). 131 In vitro, the Rreb1LacZ reporter marked a subpopulation of pluripotent embryonic stem cells (ESCs) and epiblast stem cells under self-renewing conditions and became more widely expressed as cells were differentiated by removal of the cytokine LIF or addition of FGF (Figure 1B)
Ras-responsive element-binding protein 1 (Rreb1) is initially expressed by all lineages of the pre-implantation blastocyst and is 135 downregulated within the epiblast as it transitions from a naïve to a primed state of pluripotency
Summary
55 56 Ras-responsive element-binding protein 1 (RREB1) is a zinc-finger transcription factor that acts downstream of RAS (Thiagalingam et al, 1996). It is evolutionarily conserved (Ming, Wilk, Reed, & Lipshitz, 2013), widely-expressed (FujimotoNishiyama, Ishii, Matsuda, Inoue, & Yamamoto, 1997), can function both as a transcriptional repressor and activator (Deng, Xia, Zhang, Ejaz, & Liang, 2020), and interacts with several signaling pathways, including EGFR/MAPK J. Sun & Deng, 2007), which cooperate with RREB1 in transcriptional regulation. We recently reported that chimeric mouse embryos containing Rreb mutant cells exhibit early embryonic phenotypes (Su et al, 2020), suggesting that Rreb has a role in mammalian development
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