Sonic Hedgehog基因及其在发育过程中的调控作用

Sonic Hedgehog(Shh)基因属于Hedgehog(Hh)基因家族,该家族最早在果蝇体内被发现,进化上呈高度保守状态。Sonic Hedgehog定位在7号染色体长臂远端(7q36),其通过细胞表面特殊受体Patched(Ptc)和Smoothened(Smo)被接收和传导,从而激活锌指蛋白C i/G li家族。Sonic Hedgehog基因作为重要的形态发生素,在胚胎发育、机体器官组织形成的过程中发挥了重要的作用,它的缺失或者失活会导致一系列严重的遗传疾病。其与体节、神经管、消化道、头面部、上下肢芽的发育以及肿瘤形成等有密切关系。本文主要就Sonic Hedgehog基因及其在发育中的调控作用作一综述。     

Hedgehog signaling is essential for endothelial tube formation during vasculogenesis

During embryonic development, the first blood vessels are formed through the aggregation and subsequent assembly of angioblasts (endothelial precursors) into a network of endothelial tubes, a process known as vasculogenesis. These first vessels generally form in mesoderm that is adjacent to endodermal tissue. Although specification of the angioblast lineage is independent of endoderm interactions, a signal from the endoderm is necessary for angioblasts to assemble into a vascular network and to undergo vascular tube formation. In this study, we show that endodermally derived sonic hedgehog is both necessary and sufficient for vascular tube formation in avian embryos. We also show that Hedgehog signaling is required for vascular tube formation in mouse embryos, and for vascular cord formation in cultured mouse endothelial cells. These results demonstrate a previously uncharacterized role for Hedgehog signaling in vascular development, and identify Hedgehog signaling as an important component of the molecular pathway leading to vascular tube formation.     

The mechanisms of dorsoventral patterning in the vertebrate neural tube

We describe the essential features of and the molecules involved in dorsoventral (DV) patterning in the neural tube. The neural tube is, from its very outset, patterned in this axis as there is a roof plate, floor plate, and differing numbers and types of neuroblasts. These neuroblasts develop into different types of neurons which express a different range of marker genes. Early embryological experiments identified the notochord and the somites as being responsible for the DV patterning of the neural tube and we now know that 4 signaling molecules are involved and are generated by these surrounding structures. Fibroblast growth factors (FGFs) are produced by the caudal mesoderm and must be down-regulated before neural differentiation can occur. Retinoic acid (RA) is produced by the paraxial mesoderm and is an inducer of neural differentiation and patterning and is responsible for down-regulating FGF. Sonic hedgehog (Shh) is produced by the notochord and floor plate and is responsible for inducing ventral neural cell types in a concentration-dependent manner. Bone morphogenetic proteins (BMPs) are produced by the roof plate and are responsible for inducing dorsal neural cell types in a concentration-dependent manner. Subsequently, RA is used twice more. Once from the somites for motor neuron differentiation and secondly RA is used to define the motor neuron subtypes, but in the latter case it is generated within the neural tube from differentiating motor neurons rather than from outside. These 4 signaling molecules also interact with each other, generally in a repressive fashion, and DV patterning shows how complex these interactions can be.     

The adventures of Sonic Hedgehog in development and repair. I. Hedgehog signaling in gastrointestinal development and disease

Hedgehog (Hh) proteins are members of a family of secreted signaling factors that orchestrate the development of many organs and tissues including those of the gastrointestinal (GI) tract. The requirement for Hh activity is not limited to early development but underlies the homeostasis of a number of tissues, and abnormal activity of the Hh pathway is associated with several GI malignancies. Understanding the roles and mechanisms of action of Hh signaling both in development and postnatally should thus give novel insights into potential treatments for these diseases. Here we focus on the Hh signaling pathway and its role in GI tract development and maintenance and consider the diseases resulting from aberrant Hh activity.     

Toll-like receptor 3 regulates neural stem cell proliferation by modulating the Sonic Hedgehog pathway

Toll-like receptor 3 (TLR3) signaling has been implicated in neural stem/precursor cell (NPC) proliferation. However, the molecular mechanisms involved, and their relationship to classical TLR-mediated innate immune pathways, remain unknown. Here, we report investigation of the mechanics of TLR3 signaling in neurospheres comprised of epidermal growth factor (EGF)-responsive NPC isolated from murine embryonic cerebral cortex of C57BL/6 (WT) or TLR3 deficient (TLR3(-/-)) mice. Our data indicate that the TLR3 ligand polyinosinic-polycytidylic acid (PIC) negatively regulates NPC proliferation by inhibiting Sonic Hedgehog (Shh) signaling, that PIC induces apoptosis in association with inhibition of Ras-ERK signaling and elevated expression of Fas, and that these effects are TLR3-dependent, suggesting convergent signaling between the Shh and TLR3 pathways.     

Sonic hedgehog and the molecular regulation of mouse neural tube closure

Neural tube closure is a fundamental embryonic event whose molecular regulation is poorly understood. As mouse neurulation progresses along the spinal axis, there is a shift from midline neural plate bending to dorsolateral bending. Here, we show that midline bending is not essential for spinal closure since, in its absence, the neural tube can close by a 'default' mechanism involving dorsolateral bending, even at upper spinal levels. Midline and dorsolateral bending are regulated by mutually antagonistic signals from the notochord and surface ectoderm. Notochordal signaling induces midline bending and simultaneously inhibits dorsolateral bending. Sonic hedgehog is both necessary and sufficient to inhibit dorsolateral bending, but is neither necessary nor sufficient to induce midline bending, which seems likely to be regulated by another notochordal factor. Attachment of surface ectoderm cells to the neural plate is required for dorsolateral bending, which ensures neural tube closure in the absence of sonic hedgehog signaling.