The Role of the Ets Domain Transcription Factor Erm in Modulating Differentiation of Neural Crest Stem Cells

Abstract

The transcription factor Erm is a member of the Pea3 subfamily of Ets domain proteins that is expressed in multipotent neural crest cells, peripheral neurons, and satellite glia. A specific role of Erm during development has not yet been established. We addressed the function of Erm in neural crest development by forced expression of a dominant-negative form of Erm. Functional inhibition of Erm in neural crest cells interfered with neuronal fate decision, while progenitor survival and proliferation were not affected. In contrast, blocking Erm function in neural crest stem cells did not influence their ability to adopt a glial fate, independent of the glia-inducing signal. Furthermore, glial survival and differentiation were normal. However, the proliferation rate was drastically diminished in glial cells, suggesting a glia-specific role of Erm in controlling cell cycle progression. Thus, in contrast to other members of the Pea3 subfamily that are involved in late steps of neurogenesis, Erm appears to be required in early neural crest development. Moreover, our data point to multiple, lineage-specific roles of Erm in neural crest stem cells and their derivatives, suggesting that Erm function is dependent on the cell intrinsic and extrinsic context.

Pea3 expression is regulated by FGF signaling in developing retina

“…Another member of this subfamily, Erm, has also been shown to be important in the neuronal differentiation from neural crest cells. Transfection of a dominant-negative form of Erm into chick neural crest cells blocked their differentiation into neurons, while not affecting their ability to adopt a glial fate (Paratore et al, 2002).…”

Gdnf signaling pathways within the mammalian spermatogonial stem cell niche

“…One of these factors, Etv5 (Ets Variant Gene 5), belongs to the Pea3 group of the Ets family of proteins, which are characterized by a highly conserved DNA-binding ETS domain (Sharrocks et al, 1997). Etv5 is expressed in numerous developing organs of different species (Raible and Brand, 2001;Paratore et al, 2002;Liu et al, 2003;Ouyang et al, 1999), and is over-expressed in several human tumors, in particular breast and endometrial carcinoma (Chotteau-Lelievre et al, 2004;Planaguma et al, 2005). Mice with a targeted disruption of Etv5 (Etv5 -/-) undergo a first wave of spermatogenesis during juvenile life, but show a progressive loss of spermatogenesis, with disappearance of all germ cells and a Sertoli cell-only phenotype by 10 weeks of age (Chen et al, 2005).…”

Ets Transcription Factors Control Epithelial Maturation and Transit and Crypt-Villus Morphogenesis in the Mammalian Intestine

“…Ets genetic compensation can be overcome by the use of genetically manipulated Ets factors with dominant activity. [21][22][23][24][25][26][27][28] We adopted this approach to probe the spectrum of Ets functions in the homeostasis of the intestinal crypt-villus axis in vivo. One possible dominant Ets approach, previously used by some, is the use of the Ets DNA-binding domain alone as a competitive inhibitor.…”

“…Because most Ets factors function predominantly as transcriptional activators, 1,2,4 an alternative approach, used by others, is the use of an Ets dominant repressor, composed of the Ets DNA-binding domain (DBD) and the Drosophila Engrailed repressor domain. 21,22,24 The Engrailed repressor domain functions by an active repression mechanism, 33 and should thus effect more potent blockade of endogenous Ets promoter activity than the Ets DBD alone at similar expression levels. To test this, we generated the HA epitope-tagged construct En/Erm, composed of the Engrailed repressor domain (EnRD) fused to the amino terminus of the DNA-binding domain of the Ets factor Erm (ErmDBD).…”

“…The use of genetically manipulated Ets factors with dominant activity has proven an effective way to overcome Ets genetic compensation. Such an approach has been used successfully to uncover and characterize Ets functions in a number of in vivo and in vitro systems, including lung morphogenesis, mammary tumorigenesis, and neuromuscular synapse function in the mouse, [21][22][23] neural crest differentiation, 24,25 Schwann cell survival, 26 and oncogenic cellular transformation. 27,28 In the present study, we used the dominant Ets approach to probe the spectrum of functions of Ets transcription factors in the epithelial compartment of the mammalian intestinal crypt-villus unit.…”