TLS (also known as FUS) is an RNA-binding protein that contributes the N-terminal half of fusion oncoproteins implicated in the development of human liposarcomas and leukemias. Here we report that male mice homozygous for an induced mutation in TLS are sterile with a marked increase in the number of unpaired and mispaired chromosomal axes in pre-meiotic spermatocytes. Nuclear extracts from TLS(-/-) testes lack an activity capable of promoting pairing between homologous DNA sequences in vitro, and TLS(-/-) mice and embryonic fibroblasts exhibit increased sensitivity to ionizing irradiation. These results are consistent with a role for TLS in homologous DNA pairing and recombination.
The division of cognitive labor is fundamental to all cultures. Adults have a strong sense of how knowledge is clustered in the world around them and use that sense to access additional information, defer to relevant experts, and ground their own incomplete understandings. One prominent way of clustering knowledge is by disciplines similar to those that comprise the natural and social sciences. Seven studies explored an emerging sense of these discipline-based ways of clustering of knowledge. Even 5-year-olds could cluster knowledge in a manner roughly corresponding to the departments of natural and social sciences in a university, doing so without any explicit awareness of those academic disciplines. But this awareness is fragile early on and competes with other ways of clustering knowledge. Over the next few years, children come to see discipline-based clusters as having a privileged status, one that may be linked to increasingly sophisticated assumptions about essences for natural kinds. Possible mechanisms for this developmental shift are examined.
We have used immunofluorescent localization to examine the distribution of MLH1 (MutL homolog) foci on synaptonemal complexes (SCs) from juvenile male mice. MLH1 is a mismatch repair protein necessary for meiotic recombination in mice, and MLH1 foci have been proposed to mark crossover sites. We present evidence that the number and distribution of MLH1 foci on SCs closely correspond to the number and distribution of chiasmata on diplotene-metaphase I chromosomes. MLH1 foci were typically excluded from SC in centromeric heterochromatin. For SCs with one MLH1 focus, most foci were located near the middle of long SCs, but near the distal end of short SCs. For SCs with two MLH1 foci, the distribution of foci was bimodal regardless of SC length, with most foci located near the proximal and distal ends. The distribution of MLH1 foci indicated interference between foci. We observed a consistent relative distance (percent of SC length in euchromatin) between two foci on SCs of different lengths, suggesting that positive interference between MLH1 foci is a function of relative SC length. The extended length of pachytene SCs, as compared to more condensed diplotene-metaphase I bivalents, makes mapping crossover events and interference distances using MLH1 foci more accurate than using chiasmata.
Phospholipase D (PLD) has been implicated in mitotic regulation and has been shown to be defective in cells following replicative senescence. We examined the source of changes in PLD activity in senescent human umbilical vein endothelial cells and in human diploid fibroblasts. Using fractionated cell components we found that the cytosolic components were necessary for maximum PLD activation. In comparison to low-passage cells, senescent cells showed a profound lack of PLD activatability. By recombining fractionated components from senescent and low-passage cells, we found that in senescence the membrane component is defective in activating PLD implicating either the PLD enzyme itself or its interaction with PKC and/or ARF. The sphingolipid ceramide has been implicated in mediating senescence. Treatment with ceramide resulted in a decrease in PLD activity, implicating ceramide as the mediator of the inhibition.
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