Arteriovenous Anastomosis in Human Hand Digital Skin.

While a digital arteriovenous anastomosis (Hoyer-Grosser's organ, Masson's glomus) is a well-known structure, photographic evidence of communication between arterial and venous lumens might not be demonstrated in routine histological or immunohistochemical analysis. Abundant clusters of so-called glomera were found in semi-serial sections of the distal aspect of 14 fingers obtained from 7 donated elderly cadavers. Two to six round or oval clusters were observed in each longitudinal section (over 0.3-0.6 mm in maximum diameter) in subcutaneous tissue 0.5-1.5 mm below the basal layer of the skin, whereas none were often observed in transverse sections. Lumen-to-lumen communication between arteriole and venule at 8 sites in 2 cadavers was identified in these clusters of glomera. The opening in the arteriole was large (50 µm in diameter) at 3 sites in specimens from an 80-year-old man, whereas it was small (10-30 µm) at 5 sites in those from a 91-year-old man. The arterial aspect was tightly surrounded by abundant nerve fibers expressing tyrosine hydroxylase immunoreactivity, whereas the venous part was not. No or little expression of S100 protein immunoreactivity suggested that these nerve fibers were unmyelinated. The morphology at the lumen-to-lumen communication was simple - possibly an end-to-end anastomosis - rather than a sinuous curve of arteriole opening on to a short funnel-shaped venule as seen in the standard textbooks.

Fetal development of the human trapezius and sternocleidomastoid muscles.

At present, there is no photographic evidence of splitting of the trapezius and sternocleidomastoid muscles (SCMs), which share a common anlage that extends caudally toward the limb bud in the embryo at a length of 9 mm. Therefore, the aim of the present study was to identify which structures divide the caudal end of the common anlage at the first sign of splitting into two muscles. In 11 mm-long specimens, the SCM and trapezius muscles were identified as a single mesenchymal condensation. In 15 and 18 mm-long specimens, the SCM and trapezius muscles were separated and extended posteriorly and lymphatic tissues appeared in a primitive lateral cervical space surrounded by the SCM (anterior). In 21 mm-long specimens, the lymphatic vessels were dilated and the accompanying afferents were forming connections with the subcutaneous tissue through a space between the SCM and trapezius muscles. In 27 mm-long specimens, cutaneous lymphatic vessels were evident and had entered the deep tissue between the SCM and trapezius muscles. Vascular dilation may be viewed as a result of less mechanical stress or pressure after muscle splitting.

Identification of the interleukin 4 receptor alpha gene as a direct target for p73.

p73 has a high degree of structural homology to p53 and can activate transcription of p53-responsive genes. However, analysis of p73-deficient mice revealed a marked divergence in the physiological activities of p53 family genes and distinguishes p73 from p53. Mice deficient for p73 exhibit profound defects, including hippocampal dysgenesis, chronic infection, and inflammation, as well as abnormalities in pheromone sensory pathways. p73 plays important roles in neurogenesis, sensory pathways, and homeostatic regulation. Here, we found that the interleukin 4 receptor alpha (IL-4Ralpha) gene is up-regulated by p73 but not significantly by p53 in several human cancer cell lines. IL-4Ralphatranscription is also activated in response to cisplatin, a DNA-damaging agent known to induce p73. By using small interference RNA designed to target p73, we demonstrated that silencing endogenous p73 abrogates the induction of the IL-4Ralpha gene after cisplatin treatment. Furthermore, we identified a p73-binding site in the first intron of the IL-4Ralpha gene that can directly interact with the p73 protein in vivo. This p73-binding site consists of eight copies of a 10-bp consensus p53-binding motif and is a functional response element that is relatively specific for p73 among the p53 family. p73beta promoted localized nucleosomal acetylation through recruitment of coactivator p300, indicating that p73 regulates transcription of IL-4Ralpha through the unique p73-binding site. We also found that p73beta-transfected tumor cells are sensitive to IL-4-mediated apoptosis. Our data suggest that IL-4Ralpha could mediate, in part, certain immune responses and p73-dependent cell death.

Identification of the osteopontin gene as a direct target of TP53.

The TP53 tumor suppressor gene regulates a number of genes that are involved in cell-cycle inhibition, apoptosis, and maintaining genetic stability. Recently, two genes that have a role in immunosurveillance were identified as downstream targets of TP53. These genes, TAP1 and fractalkine, may contribute to suppress tumor growth through host immunosurveillance. It has been reported that the mouse secreted phosphoprotein osteopontin (Opn) is one of the key cytokines for type 1 immune responses mediated by macrophages. It also was reported that Opn may play a role in suppressing tumor growth in vivo. Here we identified Opn as a Tp53-target gene using mRNA differential display analysis of embryonic fibroblasts from Tp53-deficient mice. Furthermore, we found that Opn expression was upregulated by DNA damage-induced Tp53 activity and by adenovirus-mediated transfer of the human TP53 gene. In addition, a luciferase assay showed that the Opn gene has a functional Tp53-responsive element in its promoter region, and a chromatin immunoprecipitation assay confirmed interaction between the Opn promoter and Tp53 protein in vivo. These results suggest that OPN is a direct transcriptional target of TP53. The TP53-directed regulation of OPN expression suggests a novel model of TP53 participation in immunosurveillance, involving interaction with the host immune system to prevent damaged cells from undergoing malignant transformation.

The p53 family member genes are involved in the Notch signal pathway.

The p53 tumor suppressor is a transcription factor that regulates cell growth and death in response to environmental stimuli such as DNA damage. p63/p51 and p73 were recently identified as members of the p53 gene family. In contrast to p53 however, p63 and p73 are rarely mutated in human cancers. Mice that lack p53 are developmentally normal, while p63 and p73 appear to play critical roles in normal development. To determine how p63 and p73 are involved in normal development, we attempted to identify target genes that are specifically regulated by p63 and/or p73 but not by p53. We found that the Jagged1 (JAG1) and Jagged2 (JAG2) genes, encoding ligands for the Notch receptors, are up-regulated by p63 and p73. Furthermore, we identified a p63-binding site in the second intron of the JAG1 gene, which can directly interact with the p63 protein in vivo, as assessed by a chromatin immunoprecipitation assay. A heterologous reporter assay revealed that this p63-binding site is a functional response element and is specific for p63. We also found a target of Notch signaling, HES-1 was up-regulated in Jurkat cells, in which Notch1 is highly expressed, when co-cultured with p63-transfected cells, suggesting that p63 can trigger the Notch signal pathway in neighboring cells. Our findings show an association between the p53 family genes and Notch signaling and suggest a potential molecular mechanism for the involvement of the p53 family genes in normal development.