The role of Pten during early embryogenesis in the mouse

Embryogenesis requires the coordination of patterning and morphogenetic events for proper tissue formation. Changes in cell shape are critical for the morphogenetic processes underlying tissue formation. I have identified a role for Pten in facilitating changes in cell shape during early embryonic development in the mouse.;Pten was identified as being important for early mouse embryogenesis when a missense mutation in Pten, M1un, was discovered in an ongoing forward genetic screen. PtenM1un/M1un embryos displayed a variety of defects including ectopic anterior-posterior (AP) axis specification, aberrant neural fold formation, a widened anterior notochord and cardia bifida. Pten m1un is a hypomorphic allele of Pten and displays defects in AP axis specification at low penetrance. Genetic strain background was also found to affect the penetrance of these phenotypes. These phenotypes were characterized in detail using a targeted null allele of Pten, Pten-/-, on the CD1 strain background and each of these phenotypes was found to be caused by defects in changes in cell shape.;Ectopic AP axis specification in Pten-/- mutant embryos is a result of defects in the movement of the anterior visceral endoderm (AVE). 50% of Pten-/- embryos display ectopic AP axis formation at e7.5, as visualized by Brachyury expression. The AVE forms at the distal tip of the embryo in the extra-embryonic visceral endoderm cell layer and then migrates to overlie the presumptive anterior side of the embryo. This migration is known to be important for inhibiting ectopic AP axis formation. The AVE fails to migrate properly in Pten -/- embryos and AVE cells in mutant embryos have abnormal shapes. Additionally, visceral endoderm cells, including AVE cells, have ectopic filamentous actin foci. Conditional removal of Pten in embryonic tissues, using the Sox2::cre transgene, confirms that Pten acts in the extraembryonic visceral endoderm for proper AP axis specification.;Pten-/- mutant embryos also display aberrant neural fold morphology. The neural plate in Pten-/- mutant embryos has a folded, flower-like appearance. Neuroepithelial cells in the neural plate fail to form a pseudo-stratified epithelium. This failure correlates with a failure to maintain cortical filamentous actin staining. This analysis indicates that Pten is important for cytoskeletal rearrangements required for cell shape changes in the early mouse embryo.