The FERM protein Epb4.1l5 is required for organization of the neural plate and for the epithelial-mesenchymal transition at the primitive streak of the mouse embryo

Abstract

During early mouse development, a single-layered epithelium is transformed into the three germ layers that are the basis of the embryonic body plan. Here we describe an ENU-induced mutation, limulus (lulu), which disrupts gastrulation and the organization of all three embryonic germ layers. Positional cloning and analysis of additional alleles show that lulu is a null allele of the FERMdomain gene erythrocyte protein band 4.1-like 5 (Epb4.1l5). During gastrulation, some cells in lulu mutants are trapped in the primitive streak at an intermediate stage of the epithelial-mesenchymal transition; as a result, the embryos have very little paraxial mesoderm. Epithelial layers of the later lulu embryo are also disrupted: definitive endoderm is specified but does not form a gut tube, and the neural plate is broad and forms ectopic folds rather than closing to make the neural tube. In contrast to zebrafish and Drosophila, in which orthologs of Epb4.1l5 control the apical localization and activity of Crumbs proteins, mouse Crumbs proteins are localized normally to the apical surface of the lulu mutant epiblast and neural plate. However, the defects in both the lulu primitive streak and neural plate are associated with disruption of the normal organization of the actin cytoskeleton. We propose that mouse Lulu (Epb4.1l5) helps anchor the actin-myosin contractile machinery to the membrane to allow the dynamic rearrangements of epithelia that mediate embryonic morphogenesis.

Mouse prickle1 , the homolog of a PCP gene, is essential for epiblast apical-basal polarity

“…First, we examined the nuclear morphology as an indicator of cell shape, using TOTO-3 staining ( Fig. 2 E and FЈ), because the dense cell packing within the epiblast hampers the direct examination of cell shape using cytoskeletal labeling, but nuclear shape varies with cell shape as a function of the cytoskeleton (22). We found that the control nuclei were ellipsoid and elongated along the AB axis, with an average length-to-width ratio of 2.49 ( Fig.…”

Epithelial cell shape is regulated by Lulu proteins via myosin-II

“…1A) (Baines, 2006;Lee, J. D. et al, 2007;Shimizu et al, 2000). The C-terminal portions of the isoforms do not have obvious homology among them.…”

“…Lulu1 mutant mice were reported to exhibit defects in shaping ingressing cells during gastrulation: Although ingressing cells normally exhibited a bottle-shaped morphology, the cells in mutant mice displayed a rounded morphology (Lee, J. D. et al, 2007). In another previous report, it was proposed that Lulu1 regulates the state of classic cadherins and integrins, and that their misregulation might be responsible for defects in gastrulation in mutants (Hirano et al, 2008).…”

“…Recently, a FERM protein, Lulu (also known as Epb41l5, erythrocyte protein band 4.1-like 5), was reported to regulate mammalian morphogenesis: Lulu mutant mice exhibited embryonic lethality with defects in gastrulation and folding of the neural plate (Garcia-Garcia et al, 2005;Hirano et al, 2008;Lee, J. D. et al, 2007). In terms of mechanistic aspects, it was proposed that Lulu downregulates the E-cadherin level, and upregulates the integrin level, thus accelerating epithelial-mesenchymal transition.…”

The ENU‐induced cetus mutation reveals an essential role of the DNA helicase DDX11 for mesoderm development during early mouse embryogenesis

“…Analysis of Sox2, a marker of neuroepithelia (Collignon et al, 1996) (George et al, 1993;Yang et al, 1993;Lee et al, 2007). Therefore, some of the neuroepithelial defects of Ddx11 cetus mutants might originate from the lack of somitic mesoderm.…”