SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion

Inactivation of TGF-beta family signaling is implicated in colorectal tumor progression. Using cis-Apc(+/Delta716) Smad4(+/-) mutant mice (referred to as cis-Apc/Smad4), a model of invasive colorectal cancer in which TGF-beta family signaling is blocked, we show here that a new type of immature myeloid cell (iMC) is recruited from the bone marrow to the tumor invasion front. These CD34(+) iMCs express the matrix metalloproteinases MMP9 and MMP2 and the CC-chemokine receptor 1 (CCR1) and migrate toward the CCR1 ligand CCL9. In adenocarcinomas, expression of CCL9 is increased in the tumor epithelium. By deleting Ccr1 in the background of the cis-Apc/Smad4 mutant, we further show that lack of CCR1 prevents accumulation of CD34(+) iMCs at the invasion front and suppresses tumor invasion. These results indicate that loss of transforming growth factor-beta family signaling in tumor epithelium causes accumulation of iMCs that promote tumor invasion.     

Nras loss induces metastatic conversion of Rb1-deficient neuroendocrine thyroid tumor

Mutations in the gene encoding the retinoblastoma tumor suppressor predispose humans and mice to tumor development. Here we have assessed the effect of Nras loss on tumor development in Rb1 heterozygous mice. Loss of one or two Nras alleles is shown to significantly reduce the severity of pituitary tumors arising in Rb1(+/-) animals by enhancing their differentiation. By contrast, C-cell thyroid adenomas occurring in Rb1(+/-) mice progress to metastatic medullary carcinomas after loss of Nras. In Rb1(+/-)Nras(+/-) animals, distant medullary thyroid carcinoma metastases are associated with loss of the remaining wild-type Nras allele. Loss of Nras in Rb1-deficient C cells results in elevated Ras homolog family A (RhoA) activity, and this is causally linked to the invasiveness and metastatic behavior of these cells. These findings suggest that the loss of the proto-oncogene Nras in certain cellular contexts can promote malignant tumor progression.     

Calcium release from frog sarcoplasmic reticulum by an imidazolyl reagent

Summary Calcium is released from the isolated heavy sarcoplasmic reticulum (SR) of frog skeletal muscle upon application of 0.1–1 mM diethylpyrocarbonate (DEP, an imidazolyl reagent). The Ca-ATPase activity of SR was suppressed by 20% in the presence of 1 mM DEP. More than 1 mM of free magnesium ion or 5 M ruthenium red eliminated the effect of DEP on calcium release but not on Ca-ATPase activity. A plausible site of DEP action is on the calcium channel.     

PPD-induced blastogenesis is auto-regulated by suppressor cells generated in vitro.

Suppressor cell induction can be demonstrated during antigen specific blastogenesis by using the same methods which have shown induction of suppressor cells by Con A. Since suppressor cells are rapidly generated during antigen specific blastogenesis, they must regulate the final level of blastogenesis induced during the seven day in vitro incubation.     

The genome sequence and structure of rice chromosome 1

The rice species Oryza sativa is considered to be a model plant because of its small genome size, extensive genetic map, relative ease of transformation and synteny with other cereal crops. Here we report the essentially complete sequence of chromosome 1, the longest chromosome in the rice genome. We summarize characteristics of the chromosome structure and the biological insight gained from the sequence. The analysis of 43.3 megabases (Mb) of non-overlapping sequence reveals 6,756 protein coding genes, of which 3,161 show homology to proteins of Arabidopsis thaliana, another model plant. About 30% (2,073) of the genes have been functionally categorized. Rice chromosome 1 is (G + C)-rich, especially in its coding regions, and is characterized by several gene families that are dispersed or arranged in tandem repeats. Comparison with a draft sequence indicates the importance of a high-quality finished sequence.     

A negative element in SMN2 exon 7 inhibits splicing in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a relatively common neurodegenerative disease caused by homozygous loss of the survival motor neuron 1 (SMN1) gene. Humans possess a linked, nearly identical gene, SMN2, which produces a functional SMN protein but at levels insufficient to compensate for loss of SMN1 (refs. 1,2). A C/T transition at position +6 in exon 7 is all that differentiates the two genes, but this is sufficient to prevent efficient exon 7 splicing in SMN2 (refs. 2,3). Here we show that the C/T transition functions not to disrupt an exonic splicing enhancer (ESE) in SMN1 (ref. 4), as previously suggested, but rather to create an exonic splicing silencer (ESS) in SMN2. We show that this ESS functions as a binding site for a known repressor protein, hnRNP A1, which binds to SMN2 but not SMN1 exon 7 RNA. We establish the physiological importance of these results by using small interfering RNAs to reduce hnRNP A protein levels in living cells and show that this results in efficient SMN2 exon 7 splicing. Our findings not only define a new mechanism underlying the inefficient splicing of SMN2 exon 7 but also illustrate more generally the remarkable sensitivity and precision that characterizes control of mRNA splicing.     

The role of sex steroid in two avian song behaviours differing in ontogenetic process

The male Bengalese finch,Lonchura striata, has two types of song behaviour (directed song, DS and undirected song, US). DS and US share a basically identical syllable repertoire, sequence pattern and tempo, but differ in the time course of appearance during the maturational process. In order to examine whether this results from a difference in testosterone (T) dependency, we studied developmental changes in the fecal T level and the amounts of DS and US during the 2–4 month period (N=7). DS appeared between 83 and 94 days of age, 4–16 days after a rise in the fecal T level. In contrast, US appeared earlier and at high frequency even when T was still at a very low level. These results suggest that DS is more dependent on the T level than US, and is not activated until the T level rises during the maturational process.