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標題: Hedgehog及Wnt訊息傳導途徑在脊椎動物性別決定所扮演的角色
The Roles of Hedgehog and Wnt Signaling Pathways in Vertebrate Sex Determination
作者: 鄭旭辰
關鍵字: 基礎研究;Sex determination genes;生物科學類;性別決定基因;訊息傳導途徑;生殖腺發育;演化;Dhh;Wnt-4;Dax 1;evolution
脊椎動物的性別決定大致可分為:(1)基因、(2)性賀爾蒙、及(3)器官型態三個層次。在基因層面,性別決定基因控制了性腺發育成睪丸或卵巢的方向。整體來說,在不同物種的脊椎動物中,性腺的發育及分化過程極為相似;然而,目前有證據顯示,雖然老鼠和雞其性腺的發育及分化過程雖然相似;但在性別決定上卻可能有截然不同的機制。以實驗用小鼠為例,在胚胎發育過程中,Dhh 僅表現在雄性線的「Sertoli 細胞」中;而且若是移除Dhh 的功能,會造成雄性的「雌性化」與不孕。在研究其分子致病機制時發現:Dhh 突變小鼠的睪丸中缺少負責製造雄性賀爾蒙的「Leydig 細胞」。因此,Dhh 在雄性性別決定及「Leydig 細胞」的分化過程中應該扮演了一個很重要的角色。雞的基因體計畫指出雞的基因中並不包含Dhh 基因;但是雞的雄性腺仍可以正常發育。因此,這個計畫想要探討Hh 訊息傳導途徑在雞的雄性生殖腺中所扮演的角色。相對於Dhh 在雄性腺中的功用,Wnt-4 控制了雌性胚胎中卵巢的分化與發育。在Wnt-4缺陷的雌性小鼠中,卵巢及雌性生殖管的發育都不完全,證明Wnt-4 對卵巢的發育非常重要。而且Wnt-4 在雞生殖腺的功能並沒有被研究過。因此,這個計畫將探討Wnt-4 訊息傳導途徑在雞的卵巢的分化與發育中所扮演的角色。此外,Dax1 也在小鼠胚胎的性別決定中扮演了一個重要的角色;過量或缺少Dax1 皆會造成雌、雄性別間的性別決定錯亂。在小鼠中,Dax1 擷抗雄性性別決定基因Sry 的作用。然而,雞的性染色體為ZW,並不包含Sry 的序列。因此,在這個計畫也將探討Dax1基因在雞的性別決定中所扮演的角色。這個計畫嘗試分別由一個「雄性性別決定基因」、一個「雌性性別決定基因」、和一個「性別決定雙重功能基因」著手,結合生物資訊學和分子生物學的方法,藉由比較小鼠和雞兩種動物雌、雄性腺發育的訊息傳導調控,進一步探討生物的「性別決定機制」。

In vertebrates with sex chromosomes, sex determination occurs at three levels: (1) genetic sexdetermination, (2) hormonal sex determination, and (3) phenotypical/morphological sexdetermination. During genetic sex determination, some sex determination genes are expressedexclusively in male or female embryos to direct the two gonad differentiation fates[1]. Generallyspeaking, the processes of gonad development are conserved among all vertebrates; however,current data suggests that the sex determination mechanisms may be very different betweenmammals and avian.In mice, Desert Hedgehog (Dhh) is expressed only in the Sertoli cells of testis. Targeted inactivationof Dhh led to male specific sterility[2]. The testes of Dhh-null mice have abnormal seminiferoustubules, and lack testosterone producing Leydig cells[3-5]. These results implicated the Dhh playsimportant roles in male sex determination. However, there is no evidence that Dhh exist in chickengenome. We hypothesize that either the other members of the Hh family substitute the function ofDhh in chicken testis or the chicken embryos evolved a Dhh-independent mechanism to sustainLeydig cell differentiation. Therefore, I propose to clarify how chicken Leydig cells differentiate inthe absence of Dhh in chicken testis development.On the other hand, Wnt-4 is required for mammalian ovary development, as conditional inactivationof Wnt-4 results in the absence of ovaries, and female reproductive ducts and the ectopic synthesisof testosterone[6]. However, the role of Wnt-4 in avian ovary development has not beencharacterized. Since the conservation of ovarian developmental processes between mouse andchicken, Wnt-4 may also plays important roles in chicken ovary development. Therefore, I intend totest the function of Wnt-4 genes during chicken embryonic gonad development.Dax 1 is another gene involved in sex determination. Transgenic expression of Dax 1 results in maleto female sex reversal[7]. In mice, it was suggested that the expression of Dax 1 is under the controlof Wnt-4 and Dax 1 functions through inhibiting the activity of Sry[7]. Since avian uses ZW sexchromosome and does not contain Sry ortholog in their genomes, I want to understand themechanism of Sry-independent sex determination by Dax 1 in chicken embryo.In this proposal, I plan to characterize the relationship of the sex determination genes, with focus onthe Hh pathway and Wnt pathway to help construct a regulatory hierarchy of sex determinationgenes that will advance our understanding in the evolutionary variations among different species invertebrates.
其他識別: NSC95-2311-B005-010-MY3
Appears in Collections:生命科學系所

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