Robustness of positional specification by the Hedgehog morphogen gradient

Spatial gradients of Hedgehog signalling play a central role in many patterning events during animal development, regulating cell fate determination and tissue growth in a variety of tissues and developmental stages. Experimental evidence suggests that many of the proteins responsible for regulating Hedgehog signalling and transport are themselves targets of Hedgehog signalling, leading to multiple levels of feedback within the system. We use mathematical modelling to analyse how these overlapping feedbacks combine to regulate patterning and potentially enhance robustness in the Drosophila wing imaginal disc. Our results predict that the regulation of Hedgehog transport and stability by glypicans, as well as multiple overlapping feedbacks in the Hedgehog response network, can combine to enhance the robustness of positional specification against variability in Hedgehog levels. We also discuss potential trade-offs between robustness and additional features of the Hedgehog gradient, such as signalling range and size regulation.     

RA and FGF Signalling Are Required in the Zebrafish Otic Vesicle to Pattern and Maintain Ventral Otic Identities

During development of the zebrafish inner ear, regional patterning in the ventral half of the otic vesicle establishes zones of gene expression that correspond to neurogenic, sensory and non-neural cell fates. FGF and Retinoic acid (RA) signalling from surrounding tissues are known to have an early role in otic placode induction and otic axial patterning, but how external signalling cues are translated into intrinsic patterning during otic vesicle (OV) stages is not yet understood. FGF and RA signalling pathway members are expressed in and around the OV, suggesting important roles in later patterning or maintenance events. We have analysed the temporal requirement of FGF and RA signalling for otic development at stages after initial anteroposterior patterning has occurred. We show that high level FGF signalling acts to restrict sensory fates, whereas low levels favour sensory hair cell development; in addition, FGF is both required and sufficient to promote the expression of the non-neural marker otx1b in the OV. RA signalling has opposite roles: it promotes sensory fates, and restricts otx1b expression and the development of non-neural fates. This is surprisingly different from the earlier requirement for RA signalling in specification of non-neural fates via tbx1 expression, and highlights the shift in regulation that takes place between otic placode and vesicle stages in zebrafish. Both FGF and RA signalling are required for the development of the otic neurogenic domain and the generation of otic neuroblasts. In addition, our results indicate that FGF and RA signalling act in a feedback loop in the anterior OV, crucial for pattern refinement.     

Cell lineage determination in the mouse

During the peri-implantation development of the mouse embryo from the blastocyst through gastrulation, Pou5f1 (OCT-4) down-regulation is closely linked to the initial step of lineage allocation to extraembryonic and embryonic somatic tissues. Subsequently, differentiation of the lineage precursors is subject to inductive tissue interactions and intercellular signalling that regulate cell proliferation and the acquisition of lineage-specific morphological and molecular characteristics. A notable variation of this process of lineage specification is the persistence of Pou5f1 activity throughout the differentiation of the primordial germ cells, which may underpin their ability to produce pluripotent progeny either as stem cells (embryonic germ cells) in vitro or as gametes in vivo. Nevertheless, intercellular signalling still plays a critical role in the specification of the primordial germ cells. The findings that primordial germ cells can be induced from any epiblast cells and that they share common progenitors with other somatic cells provide compelling evidence for the absence of a pre-determined germ line in the mouse embryo.     

The role of angiogenic growth factors in organogenesis

Angiogenic growth factors are a class of molecules which exert a fundamental role in the process of blood vessel formation. Besides vasculogenic and angiogenic properties, these compounds mediate a complex series of patterning activities during organogenesis. Angiogenic factors cooperate in the growth and development of embryo tissues in a cross-talk between endothelial cells and tissue cells. It is well established that many tissue-derived factors are involved in blood vessel formation, but there is now emerging evidence that angiogenic factors and endothelial cells themselves represent a crucial source of instructive signals to non-vascular tissue cells during organ development. Thus, angiogenic factors and endothelial cell signalling are currently believed to provide fundamental cues for cell fate specification, embryo patterning, organ differentiation and postnatal tissue remodelling. This review article will summarize some of the recent advances in our understanding of the role of angiogenic factors and endothelial cells as effectors in organ formation.     

spalt-induced specification of distinct dorsal and ventral domains is required for Drosophila tracheal patterning

Morphogenesis of the Drosophila tracheal system relies on different signalling pathways that have distinct roles in specifying both the migration of the tracheal cells and the particular morphological features of the primary branches. The current view is that the tracheal cells are initially specified as an equivalent group of cells whose diversification depends on signals from the surrounding cells. In this work, we show that the tracheal primordia are already specified as distinct dorsal and ventral cell populations. This subdivision depends on the activity of the spalt (sal) gene and occurs prior to the activity of the signalling pathways that dictate the development of the primary branches. Finally, we show that the specification of these two distinct cell populations, which are not defined by cell lineage, are critical for proper tracheal patterning. These results indicate that tracheal patterning depends not only on signalling from surrounding cells but also in the different response of the tracheal cells depending on their allocation to the dorsal or ventral domains.     

Developmental regulation of somite derivatives: muscle,cartilage and tendon

Recent research has broadened significantly our understanding of how the somite, a specialized mesodermal structure found in vertebrate embryos, gives rise to the cartilage, muscle and tendon cell lineages. The specification of somite derivatives involves the action of patterning signals secreted from adjacent tissue combined with the activation, in particular somitic compartments, of genes promoting cell lineage specification.     

FGF signalling as a mediator of lineage transitions—Evidence from embryonic stem cell differentiation

The fibroblast growth factor (FGF) signalling pathway is one of the most ubiquitous in biology. It has diverse roles in development, differentiation and cancer. Embryonic stem (ES) cells are in vitro cell lines capable of differentiating into all the lineages of the conceptus. As such they have the capacity to differentiate into derivatives of all three germ layers and to some extent the extra‐embryonic lineages as well. Given the prominent role of FGF signalling in early embryonic development, we explore the role of this pathway in early ES cell differentiation towards the major lineages of the embryo. As early embryonic differentiation is intricately choreographed at the level of morphogenetic movement, adherent ES cell culture affords a unique opportunity to study the basic steps in early lineage specification in the absence of ever shifting complex in vivo microenvironments. Thus recent experiments in ES cell differentiation are able to pinpoint specific FGF dependent lineage transitions that are difficult to resolve in vivo. Here we review the role of FGF signalling in early development alongside the ES cell data and suggest that FGF dependent signalling via phospho‐Erk activation maybe a major mediator of transitions in lineage specification. J. Cell. Biochem. 110: 10–20, 2010. © 2010 Wiley‐Liss, Inc.     

The interpretation of morphogen gradients

Morphogens act as graded positional cues that control cell fate specification in many developing tissues. This concept, in which a signalling gradient regulates differential gene expression in a concentration-dependent manner, provides a basis for understanding many patterning processes. It also raises several mechanistic issues, such as how responding cells perceive and interpret the concentration-dependent information provided by a morphogen to generate precise patterns of gene expression and cell differentiation in developing tissues. Here, we review recent work on the molecular features of morphogen signalling that facilitate the interpretation of graded signals and attempt to identify some emerging common principles.     

Mechanisms of ventral patterning in the vertebrate nervous system

Dorsoventral patterning of the neural tube has a crucial role in shaping the functional organization of the CNS. It is well established that hedgehog signalling plays a key role in specifying ventral cell types throughout the neuroectoderm, and major progress has been made in elucidating how hedgehog signalling works in this ventral specification. In addition, other molecular pathways, including nodal, retinoic acid and fibroblast growth factor signalling, have been identified as important molecular cues for ventral patterning of the spinal cord, telencephalon and eye. Here, we discuss recent advances in this field, highlighting the emerging interplay of these signalling pathways in the molecular specification of ventral patterning at different rostrocaudal levels of the CNS.     

Building the mouse gastrula: signals, asymmetry and lineages

The mouse embryo is built by assembling the progenitors of various tissue types into a body plan. Early postimplantation development involves the establishment of anatomical asymmetries and regionalized gene expression in the conceptus, the specification of tissue lineages, and the coordination of cell movement for correct positioning of the lineage progenitors before and at gastrulation. Recent findings reveal that Wnt and Tgfbeta signalling function is instrumental in delineating the anterior-posterior embryonic axis by defining the site of primitive streak formation and by directing the movement of the visceral endoderm. These signalling activities are also required for the specification of anterior and posterior fates of the epiblast cells and for the induction and navigation of the primordial germ cells.     

Primitive endoderm differentiation: from specification to epithelium formation

In amniotes, primitive endoderm (PrE) plays important roles not only for nutrient support but also as an inductive tissue required for embryo patterning. PrE is an epithelial monolayer that is visible shortly before embryo implantation and is one of the first three cell lineages produced by the embryo. We review here the molecular mechanisms that have been uncovered during the past 10 years on PrE and epiblast cell lineage specification within the inner cell mass of the blastocyst and on their subsequent steps of differentiation.     

Getting your head around Hex and Hesx1: forebrain formation in mouse

An increasing amount of evidence suggests that in mouse there are two signalling centres required for the formation of a complete neural axis: the anterior visceral endoderm (AVE), and the node and its derivatives. Embryological and genetic studies suggest that the AVE has a head-inducing activity. In contrast, the node appears to act first as a head inducer in synergy with the AVE initiating anterior neural patterning at early stages of mouse development, and later, node derivatives are necessary for maintenance and embellishment of anterior neural character. Hex and Hesx1 are homeobox genes that are expressed in relevant tissues involved in anterior patterning. The analysis of the Hex and Hesx1 mutant mice has revealed that the lack of these genes has little or no effect on the early steps of anterior neural induction. However, both genes are required subsequently for the proper expansion of the forebrain region. We suggest that disturbance in the specification of an Fgf8 signalling centre in the anterior neural ridge may account for the anterior defects observed in these mutants.     

Embryo-patterning genes and reinforcement cues determine cell fate in theArabidopsis thalianaroot

The majority of plant organs arise from groups of continuously dividing cells, the meristems. Little is known about mechanisms of cell specification in meristems. Within theArabidopsisroot meristem, the fate of every cell can be predicted accurately, and the origin of these cells during the formation of the embryonic root primordium is known. Laser ablations reveal that, despite the regularity in cell lineage, position remains important to reinforce cell specification. Genetic analysis has revealed that many genes involved in the specification of the main cell types in the root act early, during embryogenesis, and an important question is whether the same or other genes are involved in the reinforcement of specification. Sub-specification of cell types, as exemplified by epidermal root hair cell specification, involves two pathways, one of which may act to reinforce earlier patterning events mediated by the other.