Allele | EPFL Graph Search

An allele (UKˈæliːl, əˈliːl; USəˈliːl; modern formation from Greek ἄλλος állos, "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. The word is a short form of "allelomorph". "The chromosomal or genomic location of a gene or any other genetic element is called a locus (plural: loci) and alternative DNA sequences at a locus are called alleles." The simplest alleles are single nucleotide polymorphisms (SNP), but they can also be insertions and deletions of up to several thousand base pairs. Popular definitions of 'allele' typically refer only to different alleles within genes. For example, the ABO blood grouping is controlled by the ABO gene, which has six common alleles (variants). In population genetics, nearly every living human's phenotype for the ABO gene is some combination of just these six alleles. Most alleles observed result in little or no change in the functio

Placental rescue reveals a sole requirement for c-Myc in embryonic erythroblast survival and hematopoietic stem cell function

Armin Ehninger

The c-Myc protein has been implicated in playing a pivotal role in regulating the expression of a large number of genes involved in many aspects of cellular function. Consistent with this view, embryos lacking the c-myc gene exhibit severe developmental defects and die before midgestation. Here, we show that Sox2Cre-mediated deletion of the conditional c-myc(flox) allele specifically in the epiblast (hence trophoectoderm and primitive endoderm structures are wild type) rescues the majority of developmental abnormalities previously characterized in c-myc knockout embryos, indicating that they are secondary defects and arise as a result of placental insufficiency. Epiblast-restricted c-Myc-null embryos appear morphologically normal and do not exhibit any obvious proliferation defects. Nonetheless, these embryos are severely anemic and die before E12. c-Myc-deficient embryos exhibit fetal liver hypoplasia, apoptosis of erythrocyte precursors and functionally defective definitive hematopoietic stem/progenitor cells. Specific deletion of c-myc(flox) in hemogenic or hepatocytic lineages validate the hematopoietic-specific requirement of c-Myc in the embryo proper and provide in vivo evidence to support a synergism between hematopoietic and liver development. Our results reveal for the first time that physiological levels of c-Myc are essential for cell survival and demonstrate that, in contrast to most other embryonic lineages, erythroblasts and hematopoietic stem/progenitor cells are particularly dependent on c-Myc function.

2008

The Role of Nodal Processing in Pluripotent Progenitors

Anja Dietze

Nodal and its co-receptors of the EGF-CFC family are essential during chordate development, both to maintain pluripotent progenitor cells and to subsequently coordinate their allocation to the different germ layers. How these distinct Nodal activities are kept in balance is unknown. Previous work in our laboratory established that the Nodal proprotein must be cleaved by proprotein convertases (PC) to induce itself on time in the mouse epiblast. However, expression of a knock-in allele encoding a PC-resistant mutant Nodal precursor (Nr) is sufficient to induce a subset of Nodal target genes during gastrulation, including Fgf4 in the epiblast, and Bmp4 in extraembryonic ectoderm (ExE). Here, I extend these findings by showing that these NodalNr/Nr embryos also partially maintain a panel of trophoblast stem cell (TSC) markers. To better define how Nodal maintains pluripotency and how it might signal to TSCs in the ExE, and as a means to genetically uncouple Nodal production from processing, I treated cultured TSCs and NodallacZ/lacZ embryonic stem cells (ESCs) with recombinant Nodal or with cleavage-resistant mutant Nodal precursor. I show that recombinant mature Nodal stimulates Smad2 phosphorylation in both ESCs and TSCs, even though the latter do not express Nodal coreceptors of the EGF-CFC family. In contrast, recombinant Nr failed to activate the canonical Smad pathway in either cell type, and hence preferentially stimulated Jnk and p38 MAPK signaling. Yet, none of these activities were sufficient to promote self-renewal of mouse ESCs or TSCs under any of the culture conditions examined. Using lentiviral overexpression of constitutively active receptors with mutations in the Smad2,3 binding site, I observed that TSC stemness apparently can be maintained independently of Smad2,3 activation. These results suggest that mature Nodal or its unprocessed precursor likely promote the self-renewal of TSCs in vivo through a non-canonical, Smad-independent signaling pathway, but that available recombinant proteins for unknown reasons cannot fully mimic this activity in vitro, at least under the conditions examined.

EPFL2011

The Role of Nodal Processing in Pluripotent Progenitors

Anja Dietze

EPFL2011