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Alfonso Martinez Arias

Publications and source records attributed to Alfonso Martinez Arias.

15 recordsLinked to original sources
PubMed2006

Notch, a universal arbiter of cell fate decisions.

Members of the Notch family of receptors act as membrane-tethered transcription factors that are tightly associated with binary cell fate decisions. Notch signaling acts as a molecular gate that allows cells to adopt or forfeit a particular fate. Interaction of Notch with ligands triggers a sequence of proteolytic cleavages that release the intracellular domain to the nucleus; this mechanism is a target of therapies for leukemias associated with Notch activation. Although the molecular mechanism of Notch activation is well characterized, further analysis in an appropriate cellular context will provide new insight into Notch signaling.

Animals↗
PubMed2006

High-throughput localization of organelle proteins by mass spectrometry: a quantum leap for cell biology.

Cells are the fundamental building blocks of organisms and their organization holds the key to our understanding of the processes that control Development and Physiology as well as the mechanisms that underlie disease. Traditional methods of analysis of subcellular structure have relied on the purification of organelles and the painstaking biochemical description of their components. The arrival of high-throughput genomic and, more significantly, proteomic technologies has opened hereto unforeseen possibilities for this task. Recently two reports((1,2)) show how much can be gleaned from the combination of analytical centrifugation, mass spectrometry and advanced statistical techniques focused on a high-throughput analysis of the content and organization of plant and animal cells. The results reveal intriguing possibilities for the future and the possibility of mapping much of the known proteome onto our current map of the cell.

Mass Spectrometry↗
PubMed2006

Notch receptor encodes two structurally separable functions in Drosophila: a genetic analysis.

The Notch gene of Drosophila encodes a single transmembrane receptor that plays a central role in the process of lateral inhibition. This process results in the selection of individual mesodermal and neural precursors during the development of the muscular and nervous systems. The activation of Notch during lateral inhibition is mediated by the transmembrane ligand Delta (Dl) and effected by the transcription factor Suppressor of Hairless (Su(H)). The same functional cassette plays a role in other processes, in particular, the development and patterning of the wing. Genetic analysis has suggested that, in addition to the Su(H)-dependent pathway, Notch can signal in an Su(H)-independent manner. This process seems to be tightly associated with signalling by Wingless, a member of the Wnt family of signalling molecules. Here, we have analyzed further the possibility that the Notch protein encodes two different functions. To do so, we have studied the activities and genetic properties of different Notch receptors bearing deletions of specific regions of the intracellular and the extracellular domains in different developmental processes, and have sought to correlate the activity of these mutant proteins with those of existing mutants in Notch. Our results support the existence of at least two different activities of Notch each of which can be associated with specific structural domains.

Animals↗
PubMed2006

Notch synergizes with axin to regulate the activity of armadillo in Drosophila.

Cell fate decisions require the integration of various signalling inputs at the level of transcription and signal transduction. Wnt and Notch signalling are two important signalling systems that operate in concert in a variety of systems in vertebrates and invertebrates. There is evidence that the Notch receptor can modulate Wnt signalling and that its target is the activity and levels of Armadillo/beta-catenin. Here, we characterize this function of Notch in relation to Axin, a key element in the regulation of Wnt signalling that acts as a scaffold for the Shaggy/GSK3beta-dependent phosphorylation of Armadillo/beta-catenin. While Notch can regulate ectopic Wingless signalling caused by loss of function of Shaggy, it can only partially regulate the ectopic Wnt signalling induced by the loss of Axin function. The same interactions are observed in tissue culture cells where we observe a synergy in between Axin and Notch in the regulation of Armadillo/beta-catenin. Our results provide evidence for a function of Axin in the regulation of Armadillo that is different from its role as a scaffold for GSK3beta.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Filtering transcriptional noise during development: concepts and mechanisms.

The assignation of cell fates during eukaryotic development relies on the coordinated and stable expression of cohorts of genes within cell populations. The precise and reproducible nature of this process is remarkable given that, at the single-cell level, the transcription of individual genes is associated with noise - random molecular fluctuations that create variability in the levels of gene expression within a cell population. Here we consider the implications of transcriptional noise for development and suggest the existence of molecular devices that are dedicated to filtering noise. On the basis of existing evidence, we propose that one such mechanism might depend on the Wnt signalling pathway.

Animals↗
PubMed2005

High-resolution crystal structure of the human Notch 1 ankyrin domain.

The Notch receptor is part of a highly conserved signalling system of central importance to animal development. Its ANK (ankyrin) domain is required for Notch-mediated signal transduction. The crystal structure of the human Notch 1 ANK domain was solved by molecular replacement at 1.9 A (1 A=0.1 nm) resolution, and it shows that the features identified in the Drosophila homologue are conserved. The domain has six of the seven ANK repeats predicted from sequence. The putative first repeat, which has only part of the consensus and a long insertion, is disordered in both molecules in the asymmetric unit, possibly due to the absence of the RAM (RBPJkappa-associated molecule) region N-terminal to it. The exposed hydrophobic core is involved in intermolecular interactions in the crystal. Evolutionary trace analysis identified several residues that map to the hairpins of the structure and may be of functional importance. Based on the Notch 1 ANK structure and analysis of homologous Notch ANK sequences, we predict two possible binding sites on the domain: one on the concave surface of repeat 2 and the other below the hairpins of repeats 6-7.

Amino Acid Sequence↗
PubMed2005

Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity.

The establishment and stability of cell fates during development depend on the integration of multiple signals, which ultimately modulate specific patterns of gene expression. While there is ample evidence for this integration at the level of gene regulatory sequences, little is known about its operation at other levels of cellular activity. Wnt and Notch signalling are important elements of the circuitry that regulates gene expression in development and disease. Genetic analysis has suggested that in addition to convergence on the transcription of specific genes, there are modulatory cross-regulatory interactions between these signalling pathways. We report that the nodal point of these interactions is an activity of Notch that regulates the activity and the amount of the active/oncogenic form of Armadillo/beta-catenin. This activity of Notch is independent of that induced upon cleavage of its intracellular domain and which mediates transcription through Su(H)/CBF1. The modulatory function of Notch described here, contributes to the establishment of a robust threshold for Wnt signalling which is likely to play important roles in both normal and pathological situations.

Animals↗
PubMed2004

Armadillo/beta-catenin-dependent Wnt signalling is required for the polarisation of epidermal cells during dorsal closure in Drosophila.

At the end of germband retraction, the dorsal epidermis of the Drosophila embryo exhibits a discontinuity that is covered by the amnioserosa. The process of dorsal closure (DC) involves a coordinated set of cell-shape changes within the epidermis and the amnioserosa that result in epidermal continuity. Polarisation of the dorsal-most epidermal (DME) cells in the plane of the epithelium is an important aspect of DC. The DME cells of embryos mutant for wingless or dishevelled exhibit polarisation defects and fail to close properly. We have investigated the role of the Wingless signalling pathway in the polarisation of the DME cells and DC. We find that the beta-catenin-dependent Wingless signalling pathway is required for polarisation of the DME cells. We further show that although the DME cells are polarised in the plane of the epithelium and present polarised localisation of proteins associated with the process of planar cell polarity (PCP) in the wing, e.g. Flamingo, PCP Wingless signalling is not involved in DC.

Animals↗
PubMed2003

Wnts as morphogens? The view from the wing of Drosophila.

Morphogens are diffusible signalling molecules that pattern cellular fields by setting up differential gene expression in a concentration-dependent manner. Members of the Wnt family of signalling molecules are generally considered to be classical morphogens. However, a close analysis of their activity indicates that they do not fulfil all of the critera that are associated with the classical definition.

Animals↗
PubMed2002

New alleles of Notch draw a blueprint for multifunctionality.

The Drosophila Notch protein is one of a family of receptors that mediate an essential and perhaps universal function in the assignation of cell fates during development. Activation of Notch by its ligand, Delta, leads to the cleavage of the intracellular domain of the receptor. This domain relocates to the nucleus, where it combines with the transcription factor Suppressor of Hairless to regulate gene expression. In a recent report, Ramain, Heitzler and colleagues reveal the existence of a second Notch signalling activity that is independent of Suppressor of Hairless and might be used to link Notch activity to that of other signalling pathways, most notably Wingless/Wnt signalling. This link might be a central element in many processes of cell-fate assignation during development.

Alleles↗
PubMed2002

CSL-independent Notch signalling: a checkpoint in cell fate decisions during development?

During development, signalling by members of the Notch family of cell surface receptors plays a widespread role in the assignation of cell fates within the process of lateral inhibition. This function of Notch is mediated by a well-established mechanism that relies on a ligand-induced release of the intracellular domain of Notch (NICD) and the interaction of this fragment with members of the CSL (CBF1, Suppressor of Hairless, Lag-1) family of transcription factors within the nucleus. However, there is increasing evidence that Notch can signal in CSL-independent modes.

Animals↗
PubMed2002

A new dawn for an old connection: development meets the cell.

Increasingly, the attention of developmental biologists is being drawn from genes and their products towards cells, from processes mediated by linear pathways in which one protein regulates the activity of another to events that rely on multimolecular machines. Some components of these machines are partially redundant, and some have essential functions in general cellular processes. These observations invite a reassessment of the uses of genetics for analyzing the cell biology of development. In addition, the increasing ability to image live cells and their proteins reveals a complex and interesting world, forcing us to deal with new variables and objects of study. Here, we provide a glimpse of these changes and the challenges they raise.

Animals↗
PubMed2002

Planar polarity and actin dynamics in the epidermis of Drosophila.

Dorsal closure is a morphogenetic process involving the coordinated convergence of two epithelial sheets to enclose the Drosophila melanogaster embryo. Specialized populations of cells at the edges of each epithelial sheet, the dorsal-most epidermal cells, emit actin-based processes that are essential for the proper enclosure of the embryo. Here we show that actin dynamics at the leading edge is preceded by a planar polarization of the dorsal-most epidermal cells associated with a reorganization of the cytoskeleton. An important consequence of this planar polarization is the formation of actin-nucleating centres at the leading edge, which are important in the dynamics of actin. We show that Wingless (Wg) signalling and Jun amino-terminal kinase (JNK) signalling have overlapping but different roles in these events.

Actins↗