Siew-Lan Ang

Mammalian hairy and Enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis.

Mammalian hairy and Enhancer of split homolog 1 (HES1), a basic helix-loop-helix factor gene, is expressed in retinal progenitor cells, and its expression decreases as differentiation proceeds. Retinal progenitor cells infected with HES1-transducing retrovirus did not differentiate into mature retinal cells, suggesting that persistent expression of HES1 blocks retinal development. In contrast, in the retina of HES1-null mutant mice, differentiation was accelerated, and rod and horizontal cells appeared prematurely and formed abnormal rosette-like structures. Lens and cornea development was also severely disturbed. Furthermore, in the mutant retina, bipolar cells extensively died, and finally disappeared. These studies provide evidence that HES1 regulates differentiation of retinal neurons and is essential for eye morphogenesis.

An essential function of the mitogen‐activated protein kinase Erk2 in mouse trophoblast development

The closely related mitogen‐activated protein kinase isoforms extracellular signal‐regulated kinase 1 (ERK1) and ERK2 have been implicated in the control of cell proliferation, differentiation and survival. However, the specific in vivo functions of the two ERK isoforms remain to be analysed. Here, we show that disruption of the Erk2 locus leads to embryonic lethality early in mouse development after the implantation stage. Erk2 mutant embryos fail to form the ectoplacental cone and extra‐embryonic ectoderm, which give rise to mature trophoblast derivatives in the fetus. Analysis of chimeric embryos showed that Erk2 functions in a cell‐autonomous manner during the development of extra‐embryonic cell lineages. We also found that both Erk2 and Erk1 are widely expressed throughout early‐stage embryos. The inability of Erk1 to compensate for Erk2 function suggests a specific function for Erk2 in normal trophoblast development in the mouse, probably in regulating the proliferation of polar trophectoderm cells.

Nodal Antagonists in the Anterior Visceral Endoderm Prevent the Formation of Multiple Primitive Streaks

The anterior visceral endoderm plays a pivotal role in establishing anterior-posterior polarity of the mouse embryo, but the molecular nature of the signals required remains to be determined. Here, we demonstrate that Cerberus-like(-/-);Lefty1(-/-) compound mutants can develop a primitive streak ectopically in the embryo. This defect is not rescued in chimeras containing wild-type embryonic, and Cerberus-like(-/-);Lefty1(-/-) extraembryonic, cells but is rescued in Cerberus-like(-/-); Lefty1(-/-) embryos after removal of one copy of the Nodal gene. Our findings provide support for a model whereby Cerberus-like and Lefty1 in the anterior visceral endoderm restrict primitive streak formation to the posterior end of mouse embryos by antagonizing Nodal signaling. Both antagonists are also required for proper patterning of the primitive streak.

Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling

Fibroblast growth factors (FGFs) are pleiotrophic growth factors that control cell proliferation, migration, differentiation and embryonic patterning. During early zebrafish embryonic development, FGFs regulate dorsoventral patterning by controlling ventral bone morphogenetic protein (BMP) expression. FGFs function by binding and activating high-affinity tyrosine kinase receptors. FGF activity is negatively regulated by members of the Sprouty family, which antagonize Ras signalling induced by receptor tyrosine kinases. On the basis of similarities in their expression patterns during embryonic development, we have identified five genes that define a synexpression group — fgf8, fgf3, sprouty2, sprouty4, as well as a novel gene, sef (similar expression to fgf genes). Sef encodes a conserved putative transmembrane protein that shares sequence similarities with the intracellular domain of the interleukin 17 receptor. Here we show that in zebrafish, Sef functions as a feedback-induced antagonist of Ras/Raf/MEK/MAPK-mediated FGF signalling.

Nodal antagonists regulate formation of the anteroposterior axis of the mouse embryo

Patterning of the mouse embryo along the anteroposterior axis during body plan development requires migration of the distal visceral endoderm (DVE) towards the future anterior side by a mechanism that has remained unknown. Here we show that Nodal signalling and the regionalization of its antagonists are required for normal migration of the DVE. Whereas Nodal signalling provides the driving force for DVE migration by stimulating the proliferation of visceral endoderm cells, the antagonists Lefty1 and Cerl determine the direction of migration by asymmetrically inhibiting Nodal activity on the future anterior side.

The zinc finger gene Xblimp1 controls anterior endomesodermal cell fate in Spemann's organizer

The anterior endomesoderm of the early Xenopus gastrula is a part of Spemanns organizer and is important for head induction. Here we describe Xblimp1, which encodes a zinc finger transcriptional repressor expressed in the anterior endomesoderm. Xblimp1 represses trunk mesoderm and induces anterior endomesoderm in a cooperative manner with the pan‐endodermal gene Mix.1. Furthermore, Xblimp1 can cooperate with the BMP inhibitor chordin to induce ectopic heads, while a dominant‐negative Xblimp1 inhibits head formation. The head inducer cerberus is positively regulated by Xblimp1 and is able to rescue microcephalic embryos caused by dominant‐negative Xblimp1. Our results indicate that Xblimp1 is required for anterior endomesodermal cell fate and head induction.

Cloning of the mouse Sef gene and comparative analysis of its expression with Fgf8 and Spry2 during embryogenesis

We report the cloning and expression analysis of a mouse gene encoding a novel transmembrane protein. Expression of Sef is similar to that of Fgf8 and Spry2 during early embryogenesis, being prominent in the forebrain, mid-hindbrain boundary, branchial arches, somites, limb bud and tailbud of mouse embryos. These expression profiles indicate that Fgf8, Spry2 and Sef belong to a synexpression group and suggest that these genes may functionally interact during embryonic development. From E12.5 onwards, partially distinct patterns of expression of these genes are observed in the neuroepithelium, sense organs and endodermal-derived organs, that are known sites of expression of other Fgfs.

3 – Anterior-Posterior Patterning of the Mouse Body Axis at Gastrulation

This chapter discusses anterior–posterior (AP) patterning of the mouse body axis at gastrulation. The growth and differentiation of the developing mouse egg cylinder lead to the process of primary, body axis formation that sets the stage for tissue differentiation and organogenesis. One of the primary morphogenetic processes that drives development at this stage of embryogenesis is gastrulation. During gastrulation, cell proliferation, cell morphology transitions and differential adhesion, cell migation, and inductive tissue interactions combine to produce the basic body plan of the vertebrate embryo. This chapter examines the postimplantation mouse embryo from the initiation of gastrulation to the formation of the initial AP neural axis. Particular attention is focused on the process of gastrulation, the identity of organizing centers, and the genetic pathways that establish the AP body plan.