發(fā)布時(shí)間：2018-03-25 23:25

  本文選題：小鼠　切入點(diǎn)：聽(tīng)覺(jué)　出處：《復(fù)旦大學(xué)》2010年博士論文

【摘要】：上皮和間充質(zhì)組織之間的信號(hào)交流和相互作用對(duì)器官的發(fā)生和發(fā)育起重要作用。BMP4是TGFβ超家族成員中的一個(gè)亞型,BMP4及其拮抗因子Noggin調(diào)控聽(tīng)覺(jué)上皮和內(nèi)耳周圍間充質(zhì)的發(fā)生及發(fā)育。然而,BMP4在內(nèi)耳感覺(jué)上皮發(fā)育中的作用目前存在較大的爭(zhēng)議。 我們首先采用胚胎期小鼠第11.5天(E11.5)～13.5天(E13.5)的聽(tīng)覺(jué)上皮體外培養(yǎng),建立胚胎期小鼠聽(tīng)覺(jué)上皮的體外培養(yǎng)模型。所有組織的培養(yǎng)時(shí)間均等同于體內(nèi)發(fā)育至E18.5的時(shí)間(即E11.5+7 d in vitr(DIV), E12.5+6 DIV,E13.5+5 DIV),觀察聽(tīng)覺(jué)上皮形態(tài)和毛細(xì)胞分化情況。結(jié)果表明聽(tīng)覺(jué)上皮可以在體外無(wú)血清培養(yǎng)環(huán)境下存活并生長(zhǎng),其中E12.5～E13.5的聽(tīng)覺(jué)上皮培養(yǎng)后發(fā)育形態(tài)及毛細(xì)胞分化接近正常發(fā)育形態(tài),是研究毛細(xì)胞發(fā)育機(jī)制的合適模型。 采用小鼠聽(tīng)覺(jué)上皮體外無(wú)血清培養(yǎng)模型,以thermolysin獲得純聽(tīng)覺(jué)上皮作為實(shí)驗(yàn)組,帶有相鄰間充質(zhì)的聽(tīng)覺(jué)上皮為對(duì)照組,研究相鄰間充質(zhì)對(duì)聽(tīng)覺(jué)上皮發(fā)育的影響。結(jié)果顯示：各胚胎期小鼠聽(tīng)覺(jué)上皮培養(yǎng)后毛細(xì)胞的數(shù)量,對(duì)照組均高于實(shí)驗(yàn)組。E11.5+7 DIV對(duì)照組為114.43±17.92,實(shí)驗(yàn)組為66.78±20.64,兩組統(tǒng)計(jì)學(xué)差異有顯著性(P0.01)；E12.5+6 DIV對(duì)照組為519.75±98.11,實(shí)驗(yàn)組為299.71±23.91,兩組統(tǒng)計(jì)學(xué)差異有顯著性(P0.01)；E13.5+5DIV對(duì)照組為1214.38±231.88,實(shí)驗(yàn)組為1158.67±176.09,兩組統(tǒng)計(jì)學(xué)無(wú)差異。其中,在E12.5和E13.5實(shí)驗(yàn)組內(nèi)毛細(xì)胞發(fā)育不良,而E12.5對(duì)照組內(nèi)毛細(xì)胞呈1-3排不規(guī)則排列,E13.5對(duì)照組的內(nèi)毛細(xì)胞和外毛細(xì)胞出現(xiàn)明顯的界限,內(nèi)毛細(xì)胞呈縱向單排生長(zhǎng)。另外,對(duì)照組的毛細(xì)胞/支持細(xì)胞比例也均高于實(shí)驗(yàn)組。以上結(jié)果表明小鼠聽(tīng)覺(jué)上皮相鄰的間充質(zhì)組織對(duì)耳蝸感覺(jué)上早期形態(tài)發(fā)育及毛細(xì)胞分化有促進(jìn)作用。 我們采用E11.5～E13.5小鼠聽(tīng)覺(jué)上皮體外無(wú)血清培養(yǎng)模型,通過(guò)加入外源性BMP4蛋白或其抑制劑Noggin,研究BMP4在聽(tīng)覺(jué)上皮發(fā)育中的作用。加入外源性BMP4后,實(shí)驗(yàn)組的毛細(xì)胞數(shù)量均高于對(duì)照組,并呈劑量依賴性。E11.5+7 DIV對(duì)照組毛細(xì)胞數(shù)量(114.43±17.915)和bmp lOng組(150.80±29.107)有統(tǒng)計(jì)學(xué)差異(P0.05),和bmp 20ng組(198.33±40.741)有統(tǒng)計(jì)學(xué)顯著差異(P0.01),E12.5+6 DIV對(duì)照組毛細(xì)胞數(shù)量(519.75±98.112)和bmp 20ng組(650.29±173.241)有統(tǒng)計(jì)學(xué)差異(P0.05),但與bmp 10ng組(588.50±111.524)卻無(wú)統(tǒng)計(jì)學(xué)差異。E13.5培養(yǎng)后實(shí)驗(yàn)組雖然和對(duì)照組相比均無(wú)統(tǒng)計(jì)學(xué)差異,但在統(tǒng)計(jì)數(shù)量上均有增多。另外,各實(shí)驗(yàn)組的毛細(xì)胞／支持細(xì)胞比例也均高于對(duì)照組,但它們的作用與開(kāi)始培養(yǎng)的發(fā)育時(shí)期和劑量相關(guān),E11.5+7 DIV實(shí)驗(yàn)組(bmp 10ng組：0.3670±0.0616；bmp 20ng組：0.4386±0.1185)雖然在統(tǒng)計(jì)數(shù)值上有增高,但和對(duì)照組(0.3267±0.0755)卻無(wú)統(tǒng)計(jì)學(xué)差異。E12.5+6 DIV對(duì)照組(0.6657±0.0214)和bmp 10ng組(0.7038±0.0407)有統(tǒng)計(jì)學(xué)差異(P0.05),而和bmp 20ng組(0.7641±0.04521)有統(tǒng)計(jì)學(xué)顯著差異(P0.01),而E13.5+5DIV對(duì)照組(0.6820±0.0187)和bmp 20ng組(0.7944±0.0806)有統(tǒng)計(jì)學(xué)差異(P0.05),但和bmp 10ng組(0.7064±0.0967)卻無(wú)統(tǒng)計(jì)學(xué)差異。通過(guò)在培養(yǎng)中加入Brdu標(biāo)記增殖細(xì)胞,發(fā)現(xiàn)BMP4組通過(guò)增殖而來(lái)的毛細(xì)胞數(shù)量和對(duì)照組相比較并無(wú)差別。Shh和Sox2是聽(tīng)覺(jué)器官發(fā)育,特別是前感覺(jué)區(qū)(prosensory domain)形成的關(guān)鍵基因。我們發(fā)現(xiàn)加入外源性BMP4后,Sox2、Shh基因的表達(dá)明顯下調(diào),E12.5+6 DIV bmp4 20ng組的Sox2 mRNA的量為對(duì)照組的81.2%,而Shh mRNA的量?jī)H為對(duì)照組的43.7%。當(dāng)加入BMP4抑制齊(?)0.3μg/ml Noggin后,導(dǎo)致毛細(xì)胞顯著減少(E11.5+7 DIV：40.60±14.188；E12.5+6 DIV：65.14±22.974；E13.5+5 DIV：231.17±90.061)均遠(yuǎn)少于對(duì)照組,統(tǒng)計(jì)學(xué)差異有顯著性(P0.01)。這些結(jié)果表明：聽(tīng)覺(jué)上皮發(fā)育早期,Bmp4能促進(jìn)感覺(jué)前體細(xì)胞分化為毛細(xì)胞,其作用可能與抑制(?)Sox2、Shh基因表達(dá)有關(guān)。 另外,采用免疫熒光共標(biāo)技術(shù),觀察Pax2、Sox2及Proxl在小鼠內(nèi)耳發(fā)育中的時(shí)空表達(dá)模式及相互關(guān)系。結(jié)果顯示：在E9.5,Pax2主要分布在聽(tīng)泡的中間和內(nèi)側(cè),隨著前感覺(jué)區(qū)的形成,Pax2在前感覺(jué)區(qū)表達(dá)逐漸下調(diào)；當(dāng)原始的毛細(xì)胞開(kāi)始表達(dá)myosin7a時(shí),它重新選擇性上調(diào)表達(dá)于毛細(xì)胞中并維持至出生后第7天；而在前庭毛細(xì)胞中,至出生后第18天Pax2仍有表達(dá)。Sox2具有與Pax2明顯不同的表達(dá)方式,開(kāi)始主要分布在聽(tīng)泡背外側(cè),隨著前感覺(jué)區(qū)的形成,逐漸局限在感覺(jué)前體細(xì)胞,隨后在未成熟的毛細(xì)胞和支持細(xì)胞中表達(dá)；毛細(xì)胞逐漸分化成熟時(shí),在耳蝸毛細(xì)胞表達(dá)逐漸下調(diào),最后僅僅局限在支持細(xì)胞,而前庭的毛細(xì)胞和支持細(xì)胞中在出生后18天仍持續(xù)表達(dá)Sox2。Prox1表達(dá)在原始的毛細(xì)胞和未成熟的支持細(xì)胞,表達(dá)時(shí)間明顯比Sox2短。在耳蝸,Proxl僅僅短暫地表達(dá)在原始外毛細(xì)胞和發(fā)育中的Deiter細(xì)胞和Pillar細(xì)胞,在出生后18天時(shí)已無(wú)Prox1表達(dá)；而在前庭,出生時(shí)就無(wú)Proxl陽(yáng)性表達(dá)。轉(zhuǎn)錄因子Pax2、Sox2及Prox1在小鼠內(nèi)耳發(fā)育中互相聯(lián)系又有不同的時(shí)空分布特點(diǎn),表明它們?cè)趦?nèi)耳發(fā)育中具有不同的功能,特別是它們?cè)谇巴ズ投伈煌谋磉_(dá)模式表明前庭和耳蝸感覺(jué)細(xì)胞的分化形成可能具有不同的分子機(jī)制。
[Abstract]:Signal exchange and interaction between epithelial and mesenchymal tissues of organs and plays an important role in the development of.BMP4 is a subtype of TGF beta super family members, around BMP4 and its antagonist Noggin regulation of auditory epithelium and inner ear between mesenchymal and development. However, the role of BMP4 in developing auditory epithelium in the current controversial.
We used mouse embryonic day 11.5 (E11.5) to 13.5 days (E13.5) cultured in vitro cultured auditory epithelial model, the establishment of embryonic auditory epithelium in vitro. The incubation time all tissues were equivalent to E18.5 in vivo development time (E11.5+7 (DIV) d in vitr, E12.5+6 DIV, E13.5+5 DIV), observation of auditory hair cells morphology and epithelial differentiation. The results show that the auditory epithelium can be cultured in serum-free medium in vitro under the environment of the survival and growth of the E12.5 ~ E13.5 after cultured auditory epithelial morphogenesis and differentiation of hair cells close to the normal development of form, is the appropriate model to study the mechanism of hair cell development.
Mouse auditory epithelium in vitro serum-free culture model by thermolysin to obtain the pure auditory epithelia as the experimental group, with the adjacent mesenchymal auditory epithelium as control group. The effect of mesenchymal adjacent to auditory epithelial development. The results showed that the number of embryonic auditory hair cells after cultured epithelium, the control group were higher than that of the experimental group.E11.5+7 DIV control group is 114.43 + 17.92, 20.64 + 66.78 in the experimental group, the two groups had significant statistical difference (P0.01); E12.5+6 DIV group is 519.75 + 98.11, 23.91 + 299.71 in the experimental group, the two groups had significant statistical difference (P0.01); E13.5+5DIV control group is 1214.38 + 231.88. The experiment group is 1158.67 + 176.09, no statistical difference between the two groups. Among them, E12.5 and E13.5 in the experimental group in hair cell dysplasia, E12.5 group of inner hair cells are arranged in 1-3 rows of irregular arrangement, E13.5 control group of inner hair cells And the outer hair cells appear obvious boundaries, a longitudinal single row of inner hair cell growth. In addition, the control group of hair cells / Sertoli cell ratio were also higher than the experimental group. The above results indicated that mouse auditory epithelial mesenchymal tissue adjacent to cochlear sensory hair cells on early morphogenesis and differentiation have stimulative effect.
We use E11.5 to E13.5 mouse auditory epithelium in vitro serum-free culture model by adding exogenous BMP4 protein or its inhibitor Noggin, study the role of BMP4 in auditory epithelial development. After addition of exogenous BMP4, the number of hair cells in experimental group were higher than those in the control group, and showed a dose dependent.E11.5+7 DIV number in the control group. Cells (114.43 + 17.915) and BMP lOng group (150.80 + 29.107) there were significant differences (P0.05, BMP) and group 20ng (198.33 + 40.741) was statistically significant difference (P0.01), E12.5+6 DIV hair cell number in the control group (519.75 + 98.112) and BMP 20ng group (650.29 + 173.241) there were significant differences (P0.05), but with the BMP 10NG group (588.50 + 111.524) but there was no significant difference in.E13.5 culture after the experimental group and the control group while there was no significant difference in the number of statistics, but has increased. In addition, the hair cell / support proportion of cells in each experimental group It is higher than the control group, but their role and begin to develop period of training and dose related, E11.5+7 DIV group (BMP 10NG group: 0.3670 + 0.0616 BMP; group 20ng: 0.4386 + 0.1185) although the statistical numerical has increased, but the control group and (0.3267 + 0.0755) but no statistically significant difference.E12.5+6 DIV group (0.6657 + 0.0214) and BMP 10NG group (0.7038 + 0.0407) there were significant differences (P0.05), and BMP and 20ng group (0.7641 + 0.04521) was statistically significant difference (P0.01, E13.5+5DIV) and control group (0.6820 + 0.0187) and BMP 20ng group (0.7944 + 0.0806) there were significant differences (P0.05), but BMP and 10NG group (0.7064 + 0.0967) but no significant difference. By adding the Brdu marker of proliferating cells in culture, proliferation and BMP4 group by the number of hair cells compared with the control group there is no difference between.Shh and Sox2 is the auditory organ development, especially the first sensory area (pros Ensory domain) key gene formation. We found that the addition of exogenous BMP4, Sox2, Shh gene expression was down regulated, 81.2% E12.5+6 DIV BMP4 20ng Sox2 mRNA group was the control group, while Shh mRNA is only 43.7%. of the control group when adding BMP4 inhibitor (?) 0.3 g/ml Noggin after the result of hair cells was significantly reduced (E11.5+7 DIV:40.60 + 14.188 E12.5+6 + 22.974 E13.5+5; DIV:65.14; DIV:231.17 + 90.061) are far less than the control group, there was significant difference (P0.01). These results suggest that the early development of the auditory epithelium, Bmp4 can promote the differentiation of progenitor cells into sensory hair cells, which may be related to inhibition of Sox2 (?), the expression of Shh gene.
In addition, by immunofluorescence labeled technique, observation of Pax2, expression in mouse inner ear development in Sox2 and Proxl and the relationship between them. The results showed that in E9.5, Pax2 mainly distributed in the middle and medial to the bubble, as before the formation of sensory area, the expression of Pax2 in the sensory area gradually reduced; when hair cells the original expression of myosin7a, it re expression in selective hair cells and maintained up to seventh days after birth; and in the vestibular hair cells, to eighteenth days after birth, Pax2 still has the expression of.Sox2 and Pax2 with different modes of expression, beginning mainly distributed in the dorsal lateral auditory vesicle, as before the formation of sensory area the feeling was gradually limited in precursor cells, then the expression in hair cells and supporting cells in immature hair cells; differentiation gradually mature, gradually down regulated expression in cochlear hair cells, finally only in support of the cells. Hair cells and supporting cells in court in 18 days after birth is still the expression of Sox2.Prox1 in the original hair cells and immature support cells, the expression time was significantly shorter than Sox2. In the cochlea, Proxl only briefly in the original expression of outer hair cells and Deiter cells and Pillar cells in the development of the expression after birth 18 the day has no Prox1; while in the vestibule, no positive expression of Proxl was born. The transcription factor Pax2, Sox2 and Prox1 in the mouse inner ear development in contact with each other and the temporal and spatial distribution characteristics of different, indicating that they have different functions in the inner ear development, especially in the vestibular and cochlear different expression patterns show the differentiation of sensory cells of the vestibular and cochlear formation may have different molecular mechanisms.

【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2010
【分類號(hào)】：R764

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