BackgroundEndoderm organ primordia become specified between gastrulation and gut tube folding in Amniotes. Although the requirement for RA signaling for the development of a few individual endoderm organs has been established a systematic assessment of its activity along the entire antero-posterior axis has not been performed in this germ layer.Methodology/Principal FindingsRA is synthesized from gastrulation to somitogenesis in the mesoderm that is close to the developing gut tube. In the branchial arch region specific levels of RA signaling control organ boundaries. The most anterior endoderm forming the thyroid gland is specified in the absence of RA signaling. Increasing RA in anterior branchial arches results in thyroid primordium repression and the induction of more posterior markers such as branchial arch Hox genes. Conversely reducing RA signaling shifts Hox genes posteriorly in endoderm. These results imply that RA acts as a caudalizing factor in a graded manner in pharyngeal endoderm. Posterior foregut and midgut organ primordia also require RA, but exposing endoderm to additional RA is not sufficient to expand these primordia anteriorly. We show that in chick, in contrast to non-Amniotes, RA signaling is not only necessary during gastrulation, but also throughout gut tube folding during somitogenesis. Our results show that the induction of CdxA, a midgut marker, and pancreas induction require direct RA signaling in endoderm. Moreover, communication between CdxA + cells is necessary to maintain CdxA expression, therefore synchronizing the cells of the midgut primordium. We further show that the RA pathway acts synergistically with FGF4 in endoderm patterning rather than mediating FGF4 activity.Conclusions/SignificanceOur work establishes that retinoic acid (RA) signaling coordinates the position of different endoderm organs along the antero-posterior axis in chick embryos and could serve as a basis for the differentiation of specific endodermal organs from ES cells.

Early patterning of the endoderm as a prerequisite for pancreas specification involves retinoic acid (RA) as a critical signalling molecule in gastrula stage Xenopus embryos. In extension of our previous studies, we made systematic use of early embryonic endodermal and mesodermal explants. We find RA to be sufficient to induce pancreas-specific gene expression in dorsal but not ventral endoderm. The differential expression of retinoic acid receptors (RARs) in gastrula stage endoderm is important for the distinct responsiveness of dorsal versus ventral explants. Furthermore, BMP signalling, that is repressed dorsally, prevents the formation of pancreatic precursor cells in the ventral endoderm of gastrula stage Xenopus embryos. An additional requirement for mesoderm suggests the production of one or more further pancreas inducing signals by this tissue. Finally, recombination of manipulated early embryonic explants, and also inhibition of RA activity in whole embryos, reveal that RA signalling, as it is relevant for pancreas development, operates simultaneously on both mesodermal and endodermal germ layers.

Background: EGFR signaling pathway activation is a crucial step in colorectal cancer tumor progression. Results: Meprin␣ sheds the epidermal growth factor ligands EGF and TGF␣. Phosphorylation of EGFR and ERK1/2 is increased and cell proliferation and migration is enhanced after stimulation with meprin␣. Conclusion: Meprin␣ transactivates the EGFR by proteolytic processing of TGF␣ and EGF. Significance: Meprin␣ may be a therapeutic target in colorectal cancer treatment.

The concept of programmatic assessment (PA) is well described in the literature; however, studies on implementing and operationalizing this systemic assessment approach are lacking. The present case study developed a local instantiation of PA, referred to as Assessment System Fribourg (ASF), which was inspired by an existing program. ASF was utilized for a new competency-based undergraduate Master of Medicine program at the State University of Fribourg. ASF relies on the interplay of four key principles and nine main program elements based on concepts of PA, formative assessment, and evaluative judgment. We started our journey in 2019 with the first cohort of 40 students who graduated in 2022. This paper describes our journey implementing ASF, including the enabling factors and hindrances that we encountered, and reflects on our experience and the path that is still in front of us. This case illustrates one possibility for implementing PA.

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