Kim Moorwood

Distinct physiological and behavioural functions for parental alleles of imprinted Grb10

Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development, but also postnatal functions including energy homeostasis and behaviour. When the two parental alleles are unequally represented within a social group (when there is sex bias in dispersal and/or variance in reproductive success), imprinted genes may evolve to modulate social behaviour, although so far no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue-specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues.

High Basal γH2AX Levels Sustain Self‐Renewal of Mouse Embryonic and Induced Pluripotent Stem Cells

Phosphorylation of histone H2AX (γH2AX) is known to be the earliest indicator of DNA double‐strand breaks. Recently, it has been shown that mouse embryonic stem cells (mESCs) have very high basal levels of γH2AX, even when they have not been exposed to genotoxic agents. As the specialized role of high basal γH2AX levels in pluripotent stem cells is still debated, we investigated whether H2AX phosphorylation is important in maintaining self‐renewal of these cells. Here, we report that not only mESCs but also mouse‐induced pluripotent stem cells (miPSCs), have high basal levels of γH2AX. We show that basal γH2AX levels decrease upon ESC and iPSC differentiation and increase when the cells are treated with self‐renewal‐enhancing small molecules. We observe that self‐renewal activity is highly compromised in H2AX−/− cells and that it can be restored in these cells through reconstitution with a wild‐type, but not a phospho‐mutated, H2AX construct. Taken together, our findings suggest a novel function of H2AX that expands the knowledge of this histone variant beyond its role in DNA damage and into a new specialized biological function in mouse pluripotent stem cells. STEM CELLS2012;30:1414–1423

The role of scaffold proteins in JNK signalling

This paper summarises how scaffold proteins affects and regulate the JNK signalling pathway. We believe that some of these scaffold proteins, by virtue of their anchoring and catalytic properties contribute to a high degree of specificity of intra cellular signalling pathways that regulate the progression through the cell cycle.

Developmental Programming Mediated by Complementary Roles of Imprinted Grb10 in Mother and Pup

A mouse genetic study reveals that a single gene acting in both mother and offspring has a central role in the uniquely mammalian phenomenon of nutrient provisioning through the placenta and the mammary gland.

The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling.

The aim of this work is to review current knowledge relating the established cancer hallmark, sustained cell proliferation to the existence of chemicals present as low dose mixtures in the environment. Normal cell proliferation is under tight control, i.e. cells respond to a signal to proliferate, and although most cells continue to proliferate into adult life, the multiplication ceases once the stimulatory signal disappears or if the cells are exposed to growth inhibitory signals. Under such circumstances, normal cells remain quiescent until they are stimulated to resume further proliferation. In contrast, tumour cells are unable to halt proliferation, either when subjected to growth inhibitory signals or in the absence of growth stimulatory signals. Environmental chemicals with carcinogenic potential may cause sustained cell proliferation by interfering with some cell proliferation control mechanisms committing cells to an indefinite proliferative span.

Antagonistic roles in fetal development and adult physiology for the oppositely imprinted Grb10 and Dlk1 genes.

BackgroundDespite being a fundamental biological problem the control of body size and proportions during development remains poorly understood, although it is accepted that the insulin-like growth factor (IGF) pathway has a central role in growth regulation, probably in all animals. The involvement of imprinted genes has also attracted much attention, not least because two of the earliest discovered were shown to be oppositely imprinted and antagonistic in their regulation of growth. The Igf2 gene encodes a paternally expressed ligand that promotes growth, while maternally expressed Igf2r encodes a cell surface receptor that restricts growth by sequestering Igf2 and targeting it for lysosomal degradation. There are now over 150 imprinted genes known in mammals, but no other clear examples of antagonistic gene pairs have been identified. The delta-like 1 gene (Dlk1) encodes a putative ligand that promotes fetal growth and in adults restricts adipose deposition. Conversely, Grb10 encodes an intracellular signalling adaptor protein that, when expressed from the maternal allele, acts to restrict fetal growth and is permissive for adipose deposition in adulthood.ResultsHere, using knockout mice, we present genetic and physiological evidence that these two factors exert their opposite effects on growth and physiology through a common signalling pathway. The major effects are on body size (particularly growth during early life), lean:adipose proportions, glucose regulated metabolism and lipid storage in the liver. A biochemical pathway linking the two cell signalling factors remains to be defined.ConclusionsWe propose that Dlk1 and Grb10 define a mammalian growth axis that is separate from the IGF pathway, yet also features an antagonistic imprinted gene pair.

Dlk1 and Grb10, oppositely imprinted genes with antagonistic functions

Spiral cleavage is the ancestral developmental mode within the Spiralia. It covers a period of the early development characterized by asymmetric divisions with alternating division angles giving the embryo a spiral looking appearance. The position and fate of the cells are determined during the spiral cleavage thus it’s crucial for body plan formation. However, the mechanisms controlling spiral cleavage are poorly understood. To elucidate the molecular, cellular and physical mechanisms of spiral cleavage, we use the marine annelid Platynereis dumerilii as a model. We wish to unravel the role of the cytoskeleton during spiral cleavage focusing on the cytoplasmic and cortical contributions. We do this through mRNA injections of fluorescently labeled tubulin (EMTB-3XGFP) and histone (H2BmCherry) into the Platynereis zygote to label cytoplasmic elements. We imaged the live embryos with selective plane illumination microscopy (SPIM) in high-resolution, high-speed, and 3Dreconstructable manners. We processed the data with Fiji softwares (Preibisch et al., 2010, 2014, and 2015), and reconstructed this way early cell cleavages in Platynereis. Next, we extracted dynamic cellular events such as inclination of the mitotic spindles, transportation of the nuclei in the cells, and membrane deformation during cell division. Moreover, we monitored the cortical actomyosin dynamics through syn21-lifeact-mKate2 mRNA injection and imaging with spinning-disc confocal microscope. Actin is shown polarized to the micromeres prior to each division. And the cortical actomyosin chiral flow is observed in the macromeres during the spiral cleavage. Membrane deformation and actomyosin dynamics was not interfered with colchicine or nocodazole-mediated microtubule polymerization inhibition. However, actin polymerization inhibition with latrunculin A severely disrupted spindle. These suggest that the actomyosin play critical roles in both establishing cell polarity and controlling division pattern during spiral cleavages. This study provides mechanistic insights into the spiralian development and a base to compare their degree of conservation among spiralians.