Project description:Identifying the signals that regulate the survival, lineage allocation and specification of pancreas progenitors will help elucidate the embryonic origins of pancreas dysfunction and provide important cues for the efficient conversion of pluripotent stem cells into fully functional β cells. Several transcription factors regulating the conversion of the early pancreatic progenitors into terminally differentiated cells have been identified but extracellular signals regulating pancreas development are less well understood. Using a combination of genetic approaches, organotypic cultures of embryonic pancreata and genomics we have found that sphingosine-1-phosphate signalling through plays a key role in this process. S1p signalling stabilizes the Hippo pathway effector YAP to promote progenitor survival, acinar and endocrine specification. Endocrine cell specification relies on Gai subunits revealing an unexpected dependence of lineage specification on selected intracellular signalling components. Independently of YAP stabilization, S1p signalling attenuates Notch levels, thus regulating lineage allocation. These findings identify S1p signalling as a key pathway coordinating cell survival, lineage allocation and specification during pancreas development.
Project description:Identifying the signals that regulate the survival, lineage allocation and specification of pancreas progenitors will help elucidate the embryonic origins of pancreas dysfunction and provide important cues for the efficient conversion of pluripotent stem cells into fully functional β cells. Several transcription factors regulating the conversion of the early pancreatic progenitors into terminally differentiated cells have been identified but extracellular signals regulating pancreas development are less well understood. Using a combination of genetic approaches, organotypic cultures of embryonic pancreata and genomics we have found that sphingosine-1-phosphate signalling through plays a key role in this process. S1p signalling stabilizes the Hippo pathway effector YAP to promote progenitor survival, acinar and endocrine specification. Endocrine cell specification relies on Gai subunits revealing an unexpected dependence of lineage specification on selected intracellular signalling components. Independently of YAP stabilization, S1p signalling attenuates Notch levels, thus regulating lineage allocation. These findings identify S1p signalling as a key pathway coordinating cell survival, lineage allocation and specification during pancreas development.
Project description:Gene expression profiling was performed on CNS tissue from neonatal mice carrying the T9H translocation and maternal or paternal duplication of proximal Chromosomes 7 and 15. Our analysis revealed the presence of two novel paternally expressed intergenic transcripts at the PWS/AS locus. The transcripts were termed Pec2 and Pec3 for paternally expressed in the CNS.Our analysis also revealed imprinting of Magel2, Mkrn3, Ndn,Ube3a and Usp29, as well as Pec2 and Pec3 in embryonic brain, 15.5 dpc, and provided a survery of biallelically expressed genes on proximal Chromosomes 7 and 15 in embryonic and neonatal CNS. Experiment Overall Design: Eight samples were analyzed by microarray analysis using GeneChip 430B (no biological replicates). RNAs were from neonatal cortex and cerebellum, and from whole brain of 13.5 and 15.5 dpc embryos, purified from mice carrying either maternal or paternal duplication of proximal chromosomes 7 and 15.
Project description:deBack2012 - Lineage Specification in Pancreas Development
This model of two neighbouring pancreas precursor cells, describes the exocrine versus endocrine lineage specification process. To account for the tissue scale patterns, this couplet model has been extended to hundreds of coupled cells.
This model is described in the article:
On the role of lateral stabilization during early patterning in the pancreas
de Back W., Zhou JX, Brusch L
J. R. Soc. Interface 6 February 2013 vol. 10 no. 79 20120766
Abstract:
The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development.
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Project description:RNA sequencing was used to evaluate genes regulated in C3H10T1/2 cells by the G protein-coupled receptor agonist sphingosine 1-phosphate.
Project description:Pregnant mice were orally exposed to 10-5 M of bisphenolA analogs (BPAF and BADGE) from 10.5 day post-coitum (dpc) to 13.5 dpc. 13.5 dpc SSEA1 positive female germ cells from bisphenols- or vehicule- (ethanol) treated ovaries were collected. RNA were submitted to microarrays.