Meeting Report- First joint meeting of the French Society of Developmental Biology (SFBD) and of the Network of Functional Studies in Model Organisms (EFOR)

The 1st joint meeting between the French Society of Developmental Biology (SFBD) and the network of functional studies in model organisms (EFOR) took place in Paris between the 10th and the 13th of February 2014. Over the first two days, topics discussed mainly dealt with the molecular and cellular mechanisms underlying the spatio-temporal control of homeostasis and fate decisions of progenitor/stem cells in embryonic and adult tissues. Subsequently, parallel EFOR sessions dealing with specific model organisms and imaging were offered, as well as a series of talks by researchers tackling the question of how laterality is established during embryonic development in a variety of models.

Many of the talks approached the mechanisms underlying the intrinsic control of cell fate decisions. Thomas Graf (CRG, Barcelona) challenged the idea that reprogramming of B lymphocytes into pluripotent stem (iPS) is a hard task. Imposing a transient expression of the CCAAT/enhancer binding protein C/EBPa  to these cells followed by activation of Yamanaka’s transcription factors Oct4, Sox2, Klf4, and Myc (OSKM) dramatically enhanced the reprogramming efficiency into iPS cells. Notably, he showed that the C/EBPa activity pulse makes chromatin accessible to Oct4 binding through the induction of Tet2 expression, leading to the demethylation of the regulatory regions of pluripotency genes. He raised the intriguing possibility that the competence mediated by the transient activity of C/EBPa could operate during the early phases of embryogenesis. Indeed, C/EBPa is co-expressed with Oct4 from the 2-cell stage to the morula stage before becoming downregulated in the inner cell mass of the blastocyst. Along the same line of thought, Pierluigi Scerbo’s work on Xenopus in the laboratory of Laurent Kodjabachian (IBDM, France) unraveled that the MAPK pathway controls the competence of early embryonic cells to exit pluripotency and enter differentiation in response to morphogens. Pierre Cattenoz, from the laboratory of Angela Giangrande (IGBMC, France) showed that the Glide/Gcm glial determinant needs to be degraded to insure proper glial differentiation in Drosophila neural stem cells. This is promoted by interconnected loops involving its direct target and homeobox factor Repo and the lysine acetylase CBP.

The puzzling question of how a single Transcription Factor (TF) specifies discrete cell fates within a given lineage was beautifully addressed by Sonia Stefanovic from Christoffels’ laboratory (Academic Medical Center, Amsterdam, The Netherlands). She showed that Gata4 mediates both activation of Atrio Ventricular Canal (AVC) genes in the AVC and repression of these genes in myocardium. Interestingly, this dual Gata4 function relies on cell specific cooperation between Gata4 and other TFs acting downstream to regionalized signals.

The issue of how cell fate decision is temporally controlled was also addressed. Cathy Danesin from the laboratory of Cathie Soula (CBD, France) highlighted the function of Sulf1 in temporally modulating Shh activity, hence controlling the spatial arrangement of gene expression in zebrafish ventral neural progenitors. Anne Ramat from Michel Gho’s laboratory (Developmental Biology Laboratory, France) used the mechano-sensory bristle cell lineage in adult Drosophila as a model to understand how neuronal identity is temporally implemented during cell generations. She explained that early on the two Snail-related transcription factors, Escargot and Scratch, act redundantly to maintain the binary fate decision between secondary precursor cells, whereas Escargot alone is involved cell autonomously in axon patterning. Finally, the winner of the 2013 SFBD PhD’s Prize Alicia Mayeuf-Louchart from the laboratory of Margaret Buckingham (Pasteur Institute, France) gave an overview of how mouse multipotent Pax3+ dermomyotome  progenitor cells can differentiate into various cell types, including skeletal muscle, endothelial and brown adipose cells. She showed that Notch signaling directs the endothelial choice by controlling the balance between Pax3 and Foxc2. Interestingly, manipulating endothelial cell number affects myogenic progenitor migration, and FoxC1/2 also appears to be involved in brown adipose tissue differentiation.

Another axis developed in this meeting dealt with the regulation of stem cell quiescence and potential by their environment. Strikingly, the levels of Notch signaling in many stem/progenitor cells emerged as a key point within this process. Katarzyna Siudeja in the laboratory of Allison Bardin (Curie Institute, France) revealed that spontaneous somatic mutations frequently occur in aging Drosophila intestinal stem cells that result in the appearance of tumors. High rates of loss of heterogeneity are likely due to frequent mitotic recombination events. Markedly, this genetic reshuffling often impacts on the Notch signaling pathway. Shahragim Tajbakhsh’s group (Pasteur Institute, France) is interested in understanding how muscle stem/progenitors are maintained during ontogeny and regeneration. Their data indicate that constitutive Notch signaling autonomously maintains Pax7+ stem muscle cells and controls their temporal specification. Interestingly, while the Notch effector RBPJk was initially thought to influence gene expression in absence of active signaling, the Tajbakhsh group showed that RBPJk binding to the genome was actually highly dependent on the availability of the intracellular domain of Notch. Lara Dirian in Laure Bally-Cuif‘s laboratory (NeD, INAF, France) is interested in tracing the embryonic origin of the zebrafish adult pallial neural stem cells (NSC). She found that there is heterochrony in the formation of the dorso-medial and lateral domains of these adult NSC and that their embryonic progenitors differ in their sensitivity to Notch signaling. Marion Coolen, from the same laboratory, uncovered that maintaining the balance between quiescence and the activated state of these NSCs in adult was dependant on miR-9 function, possibly acting in the Notch cascade.

Other studies looking at the NSCs highlighted the importance of the cellular structure of the niche in controlling their homeostasis. On the one hand Isabel Farinas (CIBERNED, Spain) demonstrated that in the sub-ependymal zone of the adult mouse brain the quiescent population of radial glia/neural stem cells contact both the cerebrospinal fluid and blood vessels within the striatum. These contacts ensure the availability of neurotropic factors that seem to induce intrinsic regulators of the quiescent state of these stem cells. On the other hand, Andrea Brand (The Gurdon Institute, UK) tackled the issue of how the quiescence and the proliferation of neural stem cells within the Drosophila ventral nerve cord are controlled by the global nutritional status of the larva. She showed that GAP junctions between glial cells enable glia to secrete insulin-like peptides in response to amino acids in the larval diet.  This local insulin signaling induces neural stem cells to exit quiescence and resume proliferation after embryogenesis.

Several talks were based on tissue Growth in development and pathology, focusing mainly on the neoplastic behavior of stem/progenitor cells. Work from the laboratory of Maarten van Lohuisen (NKI, The Netherlands) showed that the loss of the Polycomb Repressive Complex 2 activity enhances the probability of appearance of glioblastoma in two distinct mouse models. Strikingly, upon these genetic perturbations, neural stem cells adopt an identity reminiscent of that of embryonic stem cells. An identity switch of neoplastic neuroblasts lacking Lethal (3) Malignant Brain Tumor function was reported by Cayetano Gonzales (IRB/ICREA, Spain), who gave the keynote lecture. Unexpectedly, in this context, neural progenitor cells express a set of genes normally found in the germline. The activity of some of these genes was shown to contribute the growth potential of the neoplastic neuroblasts, while others control the stability of their genome, presumably ensuring the “immortality” of these cells. Cédric Maurange (IBDM, France) pointed out that the potential of a factor to trigger Drosophila neuroblasts to adopt a neoplastic behavior is temporally restricted. Finally, Chiara Ragni (Pasteur Institute, France) identified a new component in the Fat pathway, independent of Hippo, which regulates the growth and the size of cells in the embryonic myocardium in mice.

Exciting hypotheses were proposed in the laterality session. Using zebrafish (Myriam Roussigné: CBD, France; Steve Wilson: UCL, UK) and see urchin (Thierry Lepage: UPMC, France), considerable advances have been made towards understanding how the initially asymmetric expression of Nodal impacts on the functional left/right asymmetry in organs. What triggers this asymmetric expression and which signaling pathways control its maintenance is still under investigation. Stéphane Noselli (IBV, France) showed that asymmetric hindgut looping and clockwise genital disk rotation in Drosophila is controlled by a master gene, Abd-B. This homeotic transcription factor in turn controls myosin ID expression in a spatial but not asymmetrical manner. Frédérique Peronnet (LBD-IBPS, France) showed that fluctuating asymmetry, the random deviation from perfect symmetry, reflects developmental noise and increases when Cyclin G is deregulated in Drosophila.

Finally, three other talks also reported unexpected data. First, the functional analysis of Pax3 and Pax7 by Antoine Zalc (Institute of Myology, France) brought to light that these transcription factors control the facial closure of mouse embryos by dampening the activity of a signaling pathway normally induced by environmental toxins. Second, Uri Frank (National University of Ireland, Ireland) deciphered the site and lineage origins of adult neurogenesis in the cnidarian Hydractinia. He showed that the so-called interstitial stem cells are migratory, continuously self-renew and contribute to all somatic lineages and to the germline throughout life. Finally, Oliver Hobert (Columbia University, New York, USA) presented impressive results on embryonic priming of an miRNA (lsy-6) locus that predetermines functional asymmetry in the left-right axis in postmitotic neurons  in C. elegans.

This last talk, and others, was beautifully representative of a meeting that was a hub linking cell fate decisions, chromatin accessibility, asymmetry, signaling pathways, niches, and embryology.

Thanks Laure, Angela and Myriam for organizing this exciting meeting in Paris….

To be developmentally continued….

Report written by Julie Batut (CBD, France), Vanessa Ribes (Myology Institute, France) and Jonathan Bibliowicz (CNRS-NeD/INAF, France)

Acknowledgements

We would like to thanks Dr. Patrick Blader for reading the report.

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