Abstract
During early vertebrate development, the correct establishment of the body axes is critical. The anterior pole of the mouse embryo is established when Distal Visceral Endoderm (DVE) cells migrate to form the Anterior Visceral Endoderm (AVE). Symmetrical expression of Lefty1, Cer1 and Dkk1 determines the direction of DVE migration and the future anterior side. In addition to the establishment of the Anterior-Posterior axis, the AVE has also been implicated in anterior neural specification. To better understand the role of the AVE in these processes, we have performed a differential screening using Affymetrix GeneChip technology with AVE cells isolated from cer1P-EGFP transgenic mouse embryos. We found 175 genes which were upregulated in the AVE and 36 genes in the Proximal-posterior sample. Using DAVID software, we characterized the AVE cell population regarding cellular component, molecular function and biological processes. Among the genes that were found to be upregulated in the AVE, several novel genes were identified. Four of these transcripts displaying high-fold change in the AVE were further characterized by in situ hybridization in early stages of development in order to validate the screening. From those four selected genes, one, denominated Adtk1, was chosen to be functionally characterized by targeted inactivation in ES cells. Adtk1 encodes for a serine/threonine kinase. Adtk1 null mutants are smaller and present short limbs due to decreased mineralization, suggesting a potential role in chondrogenesis during limb development. Taken together, these data point to the importance of reporting novel genes present in the AVE.
Highlights
The vertebrate body plan is generated through a series of morphogenetic and inductive processes that occur during embryonic development
Abbreviations used in this paper: Ad, anterior-distal; Anterior Visceral Endoderm (AVE), anterior visceral endoderm; DAVID, Database for Annotation, Visualization, and Integrated Discovery; Distal Visceral Endoderm (DVE), distal visceral endoderm; GO, gene ontology; Pp, posterior proximal
The importance of the AVE during mouse embryonic development has been well demonstrated; either by its removal, which leads to the loss of forebrain structures and anterior markers such as Hesx1, or by the analysis of mutants such as Cripto, Otx2, -catenin, or BMPr1 (Perea-Gomez et al, 2001, Liguori et al, 2008, Acampora et al, 2009; Huelsken et al.,“2000; Miura et al, 2010), where the DVE fails to migrate towards the anterior side of the egg cylinder resulting in the absence of a correct anterior-posterior axis formation
Summary
The vertebrate body plan is generated through a series of morphogenetic and inductive processes that occur during embryonic development. The Cerberus protein was shown to bind Xnr, BMP4 and Xwnt, thereby inhibiting their activity, while Dkk inhibits Wnt signaling by binding and antagonizing the LRP5/6 co-receptor (Mao et al, 2001; Piccolo et al, 1999). The inhibition of these three signaling pathways (Xnr, BMP and Xwnt), is considered to be essential for the specification of anterior neural character in the rostral neuroectoderm (reviewed in Belo et al, 2009).
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