ERF and ETV3L are retinoic acid-inducible repressors required for primary neurogenesis

Abstract

SUMMARYCells in the developing neural tissue demonstrate an exquisite balance between proliferation and differentiation. Retinoic acid (RA) is required for neuronal differentiation by promoting expression of proneural and neurogenic genes. We show that RA acts early in the neurogenic pathway by inhibiting expression of neural progenitor markers Geminin and Foxd4l1, thereby promoting differentiation. Our screen for RA target genes in early Xenopus development identified Ets2 Repressor Factor (Erf) and the closely related ETS repressors Etv3 and Etv3-like (Etv3l). Erf and Etv3l are RA responsive and inhibit the action of ETS genes downstream of FGF signaling, placing them at the intersection of RA and growth factor signaling. We hypothesized that RA regulates primary neurogenesis by inducing Erf and Etv3l to antagonize proliferative signals. Loss-of-function analysis showed that Erf and Etv3l are required to inhibit proliferation of neural progenitors to allow differentiation, whereas overexpression of Erf led to an increase in the number of primary neurons. Therefore, these RA-induced ETS repressors are key components of the proliferation-differentiation switch during primary neurogenesis in vivo.

Epithelial cell fate in the nephron tubule is mediated by the ETS transcription factors etv5a and etv4 during zebrafish kidney development

“…1D) (Chen, et al , 2013), the latter of which forms a winged helix-turn-helix (wHTH) motif that binds DNA elements approximately 10 basepairs long that contain the motif GGAA/T (Dittmer and Nordheim, 1998). Additionally, etv5a belongs to the conserved ETS transcription factor family, which has been shown to have roles in tissue patterning as well as in ciliogenesis (Wasylyk, et al, 1998; Kobberup, et al , 2007; Mao, et al , 2009; Znosko, et al , 2010; Chen, et al , 2013; Janesick, et al , 2013). These previously described functional roles of etv5a in tissue development, together with the early onset of etv5a expression before mature MCCs can be detected and the continued expression of etv5a throughout the MCC domain at later time points, led us to hypothesize that etv5a was involved in MCC formation in the renal progenitor field.…”

“…There is also rich evidence that etv5a and its family members are downstream of FGF signaling in a myriad of tissues (Raible and Brand, 2001; Roehl and Nüsslein-Volhard, 2001; Mao, et al, 2009; Znosko, et al , 2010; Little and McMahon, 2012; Janesick, et al , 2013). In particular, research has demonstrated that etv5b and etv4 expression is completely lost after treatment with a pan-FGF inhibitor SU5402 (Roehl and Nüsslein-Volhard, 2001).…”

“…etv5a is a member of the conserved family of E26 transformation-specific (ETS) transcription factors, categorized within the polyomavirus enhancer activator 3 (Pea3) subfamily (Oh, et al , 2012), which have been shown to have diverse roles in tissue patterning and ciliogenesis (Wasylyk, et al, 1998; Kobberup, et al , 2007; Eo, et al , 2008; Mao, et al , 2009; Znosko, et al , 2010; Chen, et al , 2013; Janesick, et al , 2013; Akagi, et al , 2015). Furthermore, the mammalian homologue of etv5a , Etv5, is known to be required for development of the murine kidney.…”

RARβ2 is required for vertebrate somitogenesis

“…RARα or RARγ knockdown in the frog, Xenopus laevis, produces specific defects in neuronal differentiation, pre-placodal ectoderm formation and axial elongation (Janesick et al, 2014(Janesick et al, , 2013(Janesick et al, , 2012Koide et al, 2001). We have shown that RARγ is required for axial elongation and for maintenance of the caudal progenitor pool (Janesick et al, 2014).…”

“…The signature chevron somite shape is found in all aquatic creatures, and is indispensable for locomotion (Rost et al, 2014). RAR loss-of-function-induced paralysis in Xenopus was previously attributed to loss of primary neurons (Janesick et al, 2013;Sharpe and Goldstone, 1997;Blumberg et al, 1997). However, other factors that control locomotion (e.g.…”