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The complexity of the cellular proteome facilitates the control of a wide range of cellular processes. Non-coding RNAs, including microRNAs and long non-coding RNAs, greatly contribute to the repertoire of tools used by cells to orchestrate various functions. Circular RNAs (circRNAs) constitute a specific class of non-coding RNAs that have recently emerged as a widely generated class of molecules produced from many eukaryotic genes that play essential roles in regulating cellular processes in health and disease. This review summarizes current knowledge about circRNAs and focuses on the functions of AMOTL1 circRNAs and AMOTL1 protein. Both products from the AMOTL1 gene have well-known functions in physiology, cancer, and other disorders. Using AMOTL1 as an example, we illustrate how focusing on both circRNAs and proteins produced from the same gene contributes to a better understanding of gene functions.

Background During mammalian cerebral cortex development, different types of projection neurons are produced in a precise temporal order and in stereotypical numbers. The mechanisms regulating timely generation of neocortex projection neurons and ensuring production in sufficient numbers of each neuronal identity are only partially understood. Results Here, we show that ephrin-B2, a member of the Eph:ephrin cell-to-cell communication pathway, sets the neurogenic tempo in the neocortex. Indeed, conditional mutant embryos for ephrin-B2 exhibit a transient delay in neurogenesis and acute stimulation of Eph signaling by in utero injection of synthetic ephrin-B2 led to a transient increase in neuronal production. Using genetic approaches we show that ephrin-B2 acts on neural progenitors to control their differentiation in a juxtacrine manner. Unexpectedly, we observed that perinatal neuron numbers recovered following both loss and gain of ephrin-B2, highlighting the ability of neural progenitors to adapt their behavior to the state of the system in order to produce stereotypical numbers of neurons. Conclusions Altogether, our data uncover a role for ephrin-B2 in embryonic neurogenesis and emphasize the plasticity of neuronal production in the neocortex.

SUMMARYMetabolic pathways, once seen as a mere consequence of cell states, have emerged as active players in dictating different cellular events such as proliferation, self-renewal and differentiation. Several studies have reported a role for folate-dependent 1-carbon (1C) metabolism in stem cells, however, its exact mode of action and how it interacts with other cues is largely unknown. Here, we report a link between the Eph:ephrin cell-cell communication pathway and 1C metabolism in controlling differentiation of neural stem cells. Transcriptional and functional analyses following ephrin stimulation revealed alterations in folate metabolism-related genes and enzymatic activity. In vitro and in vivo data indicate that Eph-B forward signaling alters the methylation state of H3K4 by regulating 1C metabolism, and locks neural stem cells in a differentiation-ready state. The functional link between cell-cell communication, metabolism and epigenetic remodeling identifies a novel triad in the control of stem cell self-renewal vs. differentiation.HIGHLIGHTS1C folate metabolism is regulated by local cell-to-cell communicationDescription of Eph-B transcriptional response in NSCEph activation decreases the expression and activity of DHFRInhibition of DHFR modifies epigenetic marks and impairs self-renewal of neural stem cellsDecreased H3K4 methylation locks neural stem cells in a pro-differentiation stateeTOC BLURBFawal et al. present evidence that Eph-B forward signaling inhibits 1C folate metabolism in neural stem cells leading to alteration of H3K4 methylation on key progenitor genes. In addition, they show that these epigenetic changes are inherited and maintained in the long term, thus locking NSC into a differentiation ready state.

Metabolic pathways, once seen as a mere consequence of cell states, have emerged as active players in dictating different cellular events such as proliferation, self-renewal, and differentiation. Several studies have reported a role for folate-dependent one-carbon (1C) metabolism in stem cells; however, its exact mode of action and how it interacts with other cues are largely unknown. Here, we report a link between the Eph:ephrin cell-cell communication pathway and 1C metabolism in controlling neural stem cell differentiation. Transcriptional and functional analyses following ephrin stimulation revealed alterations in folate metabolism-related genes and enzymatic activity. In vitro and in vivo data indicate that Eph-B forward signaling alters the methylation state of H3K4 by regulating 1C metabolism and locks neural stem cell in a differentiation-ready state. Our study highlights a functional link between cell-cell communication, metabolism, and epigenomic remodeling in the control of stem cell self-renewal.

SUMMARY STATEMENTThis article by Laussu et al. describes a role for Eph:ephrin signaling in controlling the identity of neural progenitors in the ventral spinal cord.Early specification of progenitors of the ventral spinal cord involves the morphogen Sonic Hedgehog which induces distinct progenitor identities in a dose-dependent manner. Following these initial patterning events, progenitor identities have to be maintained in order to generate appropriate numbers of progeny. Here we provide evidence that communication via Eph:ephrin signaling is required to maintain progenitor identities in the ventral spinal cord. We show that ephrinB2 and ephrinB3 are expressed in restricted progenitor domains in the ventral spinal cord while several Eph receptors are more broadly expressed. Further, we provide evidence that expression ofEfnb3andEphA4is controlled by Shh. Genetic loss-of-function analyses indicate that expression of ephrinB2 and ephrinB3 is required to control progenitor identities and in vitro experiments reveal that activation of Eph forward signaling in spinal progenitors up-regulates the expression of the identity transcription factor Nkx2.2. Altogether our results indicate that cell-to-cell communication is necessary to control progenitor identity in the ventral spinal cord.