Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice

Medulloblastoma is a cerebellar tumor that can arise through aberrant activation of Sonic hedgehog (Shh) signaling, which normally regulates cerebellar granule cell proliferation. Mutations of the Shh receptor PATCHED (PTCH) are associated with medulloblastomas, which have not been found to have loss of PTCH heterozygosity. We address whether patched (Ptc) heterozygosity fundamentally alters granule cell differentiation and contributes to tumorigenesis by increasing proliferation and/or decreasing apoptosis in Ptc+/- mice. Our data show that postnatal Ptc+/- mouse granule cell precursor growth is not globally altered. However, many older Ptc+/- mice display abnormal cerebellar regions containing persistently proliferating granule cell precursors. Since fewer Ptc+/- mice form medulloblastomas, these granule cell rests represent a developmentally disrupted, but uncommitted stage of tumorigenesis. Although Ptc+/- mouse medulloblastomas express neurodevelopmental genes, they diverge from granule cell differentiation in their discordant coexpression of postmitotic markers despite their ongoing growth. Like human medulloblastomas, mouse tumors with reduced levels of the neurotrophin-3 receptor, trkC/Ntrk3, display decreased apoptosis in vivo, illustrating the role of TrkC in regulating tumor cell survival. These results indicate that Ptc heterozygosity contributes to tumorigenesis by predisposing a subset of granule cell precursors to the formation of proliferative rests and subsequent dysregulation of developmental gene expression.     

干旱地区斑块状植被格局形成的水分驱动机制及其研究进展

斑块状分布是植被在水分匮乏环境中长期适应的结果,其演替过程可以作为生态系统响应气候变化和人类活动产生突变的"指示器"。本文通过对斑块状植被的起源、生态水文过程及其对干旱区植被恢复的启示等方面进行综述,提出了我国干旱区植被恢复中目前尚存在的主要问题。认为斑块状植被的形成可能受气候变化、人类活动、植物自身的生物学特性及其对环境胁迫的适应等方面的影响,但不是主要因素,植被斑块和裸地斑块之间在不同空间尺度的水分再分配是其在干旱半干旱地区形成并且能够维持稳定的关键。斑块状植被是一个高效的雨水集流系统,裸地斑块是整个系统径流的"源",而植被斑块是整个系统径流的"汇",保护植被斑块的同时维持一定面积的裸地对于整个生态系统的稳定都具有极其重要的意义。斑块状植被也是一个非常脆弱的生态系统,气候的剧烈波动以及人类的过度活动都可能导致生态系统功能丧失,最终产生不可逆转的影响,因此需要加以严格保护。     

Hedgehog-mediated paracrine interaction between hepatic stellate cells and marrow-derived mesenchymal stem cells

During liver injury, bone marrow-derived mesenchymal stem cells (MSCs) can migrate and differentiate into hepatocytes. Hepatic stellate cell (SC) activation is a pivotal event in the development of liver fibrosis. Therefore, we hypothesized that SCs may play an important role in regulating MSC proliferation and differentiation through the paracrine signaling pathway. We demonstrate that MSCs and SCs both express hedgehog (Hh) pathway components, including its ligands, receptors, and target genes. Transwell co-cultures of SCs and MSCs showed that the SCs produced sonic hedgehog (Shh), which enhanced the proliferation and differentiation of MSCs. These findings demonstrate that SCs indirectly modulate the activity of MSCs in vitro via the Hh pathway, and provide a plausible explanation for the mechanisms of transplanted MSCs in the treatment of liver fibrosis.     

The solitary (primary) cilium--a mechanosensory toggle switch in bone and cartilage cells

Osteocytes and articular chondrocytes sense and respond to the strains imposed on bones and joints by various activities such as breathing and walking. This mechanoresponsiveness is needed to maintain bone and cartilage microstructure and strength. In bone the large number of osteocytes form a vast osteointernet in which the gap junctionally interconnected members are lodged in an extensive lacunocanalicular network. The much smaller number of articular chondrocytes are not interconnected in a chondrointernet. Instead, they are separately lodged in capsules called chondrons. While there are many possible strain-sensing devices, it now appears that the non-motile solitary (primary) cilia protruding like aerials from osteocytes (as well as osteoblasts) and chondrocytes are switches that when toggled by cyclical pulses of lacunocanalicular fluid or cartilage compression send signals such as Ca²⁺ surges into the cell to trigger a cascade of events that include appropriate gene activations to maintain and strengthen bone and cartilage. Moreover, the chondrocyte cilium with its Ihh(Indian hedgehog)-activated Smo receptor is a key player along with PTHrP in endochondral bone formation.     

Retinal morphogenesis in Drosophila: Hints from an eye-specific decapentaplegic allele

decapentaplegic (dpp) regulates many aspects of imaginal disc growth and patterning in Drosophila. We have analyzed the phenotype of an eye-specific dpp allele, dpp^blk, which causes a reduction in the size of the retina due to a loss of ventral ommatidia. Prior to the onset of differentiation, dpp^blk eye discs are normal regarding size, shape, and ability to express dorsal and ventral markers. However, expression of a dpp-lacZ reporter is reduced at the ventral margin. Additional dorsoventral asymmetry appears during retinal differentiation: the morphogenetic furrow (MF) initiates normally at the posterior tip of the disc, but fails to propagate into the ventral epithelium. This defect can be rescued by increasing dpp expression along the ventral margin by local removal of patched function. We propose that the primary defect in dpp^blk is an inability to activate dpp expression properly at the ventral margin. This has two consequences: it prevents initiation from the ventral margin, and it renders the ventral epithelium unresponsive to differentiation signals emanating from the MF. Dev. Genet. 20:197–207, 1997. © 1997 Wiley-Liss, Inc.     

The mir‐7 and bag of marbles genes regulate Hedgehog pathway signaling in blood cell progenitors in Drosophila larval lymph glands

Hedgehog (Hh) pathway signaling is crucial for the maintenance of blood cell progenitors in the lymph gland hematopoietic organ present in Drosophila third instar larvae. Previous studies from our lab have likewise shown the importance of the mir‐7 and bag of marbles (bam) genes in maintaining the progenitor state. Thus, we sought to investigate a possible interaction between the Hh pathway and mir‐7/bam in the prohemocyte population within this hematopoietic tissue. Gain of function mir‐7 was able to rescue a blood cell progenitor depletion phenotype caused by Patched (Ptc) inhibition of Hh pathway signaling in these cells. Similarly, expression of a dominant/negative version of Ptc was able to rescue the severe reduction of prohemocytes due to bam loss of function. Furthermore, we demonstrated that Suppressor of fused [Su(fu)], another known inhibitor of Hh signaling, likely serves as a translational repression target of the mir‐7 miRNA. Our results suggest the mir‐7/bam combination regulates the Hh signaling network through repression of Su(fu) to maintain hemocyte progenitors in the larval lymph gland.