成形素是一類分泌性信號分子，它們在形成一定形狀和尺寸的器官過程中起著關(guān)鍵作用?，F(xiàn)在，辛辛那提兒童醫(yī)院醫(yī)學(xué)中心的研究人員已經(jīng)知道這種分子在生物體中的工作方式,，即擴(kuò)散方式,。這些新發(fā)現(xiàn)公布在10月15日的Cell上。
成形素在器官的形成中其重要作用,，但是當(dāng)這些分子發(fā)生功能故障時就可能造成器官缺陷和癌癥,。目前對成形素的工作方式有多種假說，其中包括細(xì)胞外擴(kuò)散和轉(zhuǎn)細(xì)胞理論（transcytosis）,。細(xì)胞外擴(kuò)散理論認(rèn)為成形素在細(xì)胞表面移動,；轉(zhuǎn)細(xì)胞理論則認(rèn)為細(xì)胞通過內(nèi)吞作用轉(zhuǎn)移成形素分子。成形素有很多種,，在新的研究中,，研究人員集中研究了TGF beta蛋白家族的工作方式。
兒童醫(yī)院醫(yī)學(xué)中心的林新華博士和同事在研究中用果蠅作為研究的模型,，并且對果蠅的Dpp（Decapentaplegic）蛋白進(jìn)行了研究,。Dpp是一種與人類TGF beta蛋白結(jié)果相似的成形素分子,。Dpp的作用是指導(dǎo)果蠅翅膀的形成。研究組證明Dpp成形素分子主要分布在細(xì)胞表面,，這意味著Dpp成形素通過細(xì)胞外擴(kuò)散機(jī)制來運動,。
研究人員還用抑制內(nèi)吞作用并檢測Dpp成形素的運動的方法對這種推測進(jìn)行了驗證。他們發(fā)現(xiàn)抑制內(nèi)吞作用干擾了細(xì)胞轉(zhuǎn)換Dpp信號的能力,，但是卻不會阻礙Dpp橫跨細(xì)胞的運動,。這個實驗也揭示出了內(nèi)吞作用在Dpp傳遞信號活動中的作用。
這項研究使我們進(jìn)一步了解了器官形成的機(jī)制,，并且還可能促進(jìn)器官缺陷和癌癥的治療。這些對成形素作用機(jī)制的新了解將會促進(jìn)對相關(guān)疾病的新治療藥物的研發(fā),。
有關(guān)這個基因的詳細(xì)功能描述：
decapentaplegic
Function
decapentaplegic is responsible for dorsal/ventral polarity in the fly. In a second phase of its activity, as segments appear, dpp functions in the definition of boundaries between segmental compartments. As part of this process, dpp, along with wingless and hedgehog, defines the position of future limbs, including wings, legs and antenna. dpp also has an independent role in the structuring of the mesoderm. Later, during the final process of appendage development, and acting downstream of engrailed and hedgehog, dpp defines boundaries between appendage compartments assuring correct anterior/posterior polarity. dpp has an analogous function in the development of the eye, where it is primarily responsible for the progression of the morphogenetic furrow, the induction site of the Drosophila retina.
The effects on the dorsal-most region of the fly are regulated by Saxophone in conjuction with Thick veins and Punt. Without DPP signals through Saxophone, the amnioserosa, the most dorsal ectodermal tissue, does not develop properly and dorsal closure, the sealing of a dorsal "hole" in the developing embryo does not take place. The dorsal region is ventralized, and it develops characteristics of the ventral neuroectoderm.
The initial effects of DPP on the heart and on visceral mesoderm (gut muscles) are mediated by Thick veins and Punt. An early and important event in the subdivision of the mesoderm is the restriction of tinman expression to dorsal mesodermal cells, the precursors of heart cells.
DPP also induces local differentiation in the endoderm (Manak J. R., 1995). The actions of dpp on gene activation are not always positive. dpp actively suppresses the development of the proventriculus, confining it to the foregut.
Secreted in an anterior to posterior stripe in the trunk, DPP intersects wingless expressing cells under the control of hedgehog in segmentally repeated dorsal/ventral stripes. All three proteins are needed to allocate cells for the formation of imaginal discs, which will ultimately develop into appendages. This process involves induction of distal-less and aristaless, both of which are needed to specify the tips of appendages (Campbell G., 1993 and Diaz-Benjumea F. J., 1994).
Protein
The carboxy-terminal 100 amino acids have 25-40% homology to human and porcine TGFbeta, Inhibin A and Inhibin B. The homologous region is preceeded by three arginine dimers that each function as proleolytic cleavage sites (Padget R. W., 1987).
Subcellular location
Secreted
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Expression Patterns
Early dpp expression pattern in the ectoderm is dynamic, consisting of three phases. Phase I, in which dpp is expressed in a broad dorsal domain, depends on elements in the dpp second intron that interact with the Dorsal transcription factor to repress transcription ventrally. In contrast, in phases II and III, dpp is expressed first in broad longitudinal stripes (phase II) and subsequently in narrow longitudinal stripes (phase III) (Schwyter D. H., 1995). dpp is also expressed in the visceral mesodermal midgut, where it regulates formation of caeca. DPP has a major role in compartment formation between visceral segments and is expressed there during the process of segmentation (Manek J. R., 1994).
dpp and Ubx proteins are expressed in overlapping domains in the visceral mesoderm in parasegment 7. The dpp domain extends further anteriorly by half a parasegment. (Reuter R., 1990)
dpp expression in the gut, at least some of which is presumably endodermal, includes the presumptive pharynx, a portion of the presumptive exophagus, the primordia of the gastric caeca, the parasegment 7 region of the midgut, and a portion of the presumptive hindgut. As these expression patterns are generated from promoter fragments, the finding of DPP expression in the endoderm should remain controvertial until confirmed (Jackson P. D., 1994).
dpp protein is present in the visceral mesoderm at and anterior to the second midgut constriction from embryonic stage 14. By stage 16, dpp protein surrounds the adjacent endoderm cells. (Panganiban G., 1990)
Development of the Drosophila retina occurs asynchronously. The leading edge of differentiation, its front marked by the morphogenetic furrow, progresses across the eye disc epithelium over a 2 day period. The mechanism by which this front advances suggest that developing retinal cells behind the furrow drive the progression of morphogenesis utilizing the products of the hedgehog and decapentaplegic genes. Analysis of hh and dpp genetic mosaics indicates that the products of these genes act as diffusible signals in this process. Expression of dpp in the morphogenetic furrow is closely correlated with the progression of the furrow under a variety of conditions. HH, synthesized by differentiating cells, induces the expression of dpp, which appears to be a primary mediator of furrow movement (Heberlein U., 1993).
dpp is expressed during oogenesis in anterior follicle cells. Expression is first detectable at the end of stage 8 in approximately 20 to 30 somatic follicle cells at the anterior tip of the egg chamber. (Twombly V., 1996).
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Sequences
GenBank
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Regulatory Regions
Manak, J. R., Mathies, L. D. and Scott, M. P. Regulation of a decapentaplegic midgut enhancer by homeotic proteins. Development 120, 3605-3619 (1994):
DMDPPME D.melanogaster dpp midgut enhancer DNA. : regulation by homeotic proteins
Regulatory element Localisation of element Trans-regulatory factor (TRANSFAC links) Reference
negative regulatory element 5'-flanking region ENGRAILED Sanicola et al., 1995
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Regulatory Connections
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Protein & Transcript Data
FlyBase
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Links
FlyBase ID: FBgn0000490
For detailed review about this gene see THE INTERACTIVE FLY Data Base.
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