Smad4 in osteoblasts exerts a differential impact on HSC fate depending on osteoblast maturation stage.

Osteoblasts (OBs) are indispensable for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow microenvironment. Here we investigated how Smad4 modulates HSC fate at distinct stages of OB development. For this, we conditionally knocked out Smad4 in cells expressing type I collagen (Col1a1) and osteocalcin (OC), respectively. Col1a1-expressing OBs were widely present in both the trabecular and cortical compartment, whereas OC-expressing OBs were predominantly located in the cortical compartment. HSCs from Col1a1 mutants displayed senescence-associated phenotypes. OC mutants did not exhibit HSC senescence-related phenotypes, but instead showed preferential HSC death. Of note, stromal cell-derived factor 1 expression was lower in Col1a1 mutants than control littermates, suggesting potential impairment of CXCR4-CXCL12-mediated HSC retention. Disruption of the CXCR4-CXCL12 axis by AMD3100 administration led to an increase in the senescence-associated ß-galactosidase activity and low competitive potential. Collectively, our findings indicate that deletion of Smad4 in OBs differentially modulates HSC fate in a stage-dependent manner.

mRNA expression of netrin-1, an axon guidance protein in chick and rat embryos.

The guidance of axons to their targets in developing neurons is believed to be mediated by diffusible chemotropic factors secreted by target cells. In vertebrates, commissural axons pioneer a circumferential pathway to the floor plate at the ventral midline of the embryonic spinal cord. Floor plate cells secrete a diffusible factor called 'netrin', that promotes the outgrowth of axons in the embryonic chick brain. The cloning of cDNAs encoding netrin showed that it is homologous to UNC-6, a laminin-related protein which is required for the circumferential migration of cells and axons in Caenorhabditis elegans. The differential expression of the netrin-1 gene was examined by slot blot analysis in various chick embryonic tissues, especially in the embryonic brain at various developmental stages. The netrin-1 transcript was most strongly expressed in the brain at the early developmental stages of E3 to E7 that corresponds to the time of emergence and full generation of commissural axons in the chick brain. In order to study whether netrin-1 can act as a global cue to guide all circumferentially migrating axons in the CNS, the localization of netrin-1 mRNA expression in the rat embryos was examined by in situ hybridization. Netrin-1 mRNA was detected in the neuroepithelial cells of the ventral midline along the entire rostrocaudal axis of the E18 rat embryo. These results suggest that netrin-1 functions as a global guidance cue for ventrally directed circumferential migrations toward the midline at all axial levels where the floor plate is found.

Mycosis fungoides mimicking inflammatory linear verrucous epidermal nevus.

We experienced an unusual case of mycosis fungoides with the clinical and histological features mimicking inflammatory linear verrucous epidermal nevus (ILVEN) in an 11-year-old boy. Localized linear multiple pruritic verrucous confluent papules and plaques appeared on the his left elbow, forearm and hand for 7 months. Skin biopsies showed characteristic findings of mycosis fungoides (e.g. Pautrier's microabscesses, follicular epitheliotropism, wiry bundles of collagen, etc.). T-cell receptor gene rearrangement analysis in the lesional skin demonstrated rearrangement of the gamma chain. RePUVA (systemic PUVA with retinoic acid) therapy improved his skin lesions and pruritus, but these progressed after discontinuation of treatment. Thus, lesions mimicking ILVEN can be an unusual and potentially misleading presentation of mycosis fungoides.

Interferon gamma stimulates beta-secretase expression and sAPPbeta production in astrocytes.

Neurons, but not astrocytes, are known as the major source of Abeta, because astrocytes express low levels of putative beta-secretase (BACE). Astrocytes near senile plaque cores show enhanced levels of BACE protein expression, however, suggesting that astrocytes can contribute to Abeta production under pathological conditions. To investigate factors that stimulate BACE protein expression in astrocytes, we tested the effects of interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) on BACE protein expression in U373MG astrocytoma cells and primary astrocyte cultures from Tg2576 mouse brains. BACE protein expression and sAPPbeta production were dramatically increased, without changes in holo APP levels, following IFN-gamma treatment in both cell types. AG490, which is a blocker of IFN-gamma-induced STAT signaling, decreased IFN-gamma-induced BACE protein expression and sAPPbeta production in a dose-dependent manner. These results show that astrocytes are capable of expressing BACE and producing sAPPbeta in response to certain stimulating factors, and IFN-gamma is one such factor.