缺氧如何诱导果蝇气管发生分化

昆虫体内的循环系统一般不参与氧气运输，各组织和器官所需的氧气直接由气
管系统供应。与哺乳动物的血管生成过程相似，昆虫气管的末端也能够产生分
枝并侵入缺氧组织内。

以往研究表明，果蝇体内处于缺氧状态的细胞会产生Bnl，这是成纤维细胞生长
因子的同源体，其受体Btl位于气管细胞表面，Bnl能够诱导气管细胞分枝伸入
缺氧组织内，这就是气管生成的“Bnl中心模式”。

Centanin等人的研究工作进一步揭示了气管末端分枝的形成机制，果蝇气管末
端的细胞本身对缺氧环境也非常敏感，缺氧条件下，对氧含量敏感的脯氨酰羟
化酶Fatiga能够增加缺氧诱导因子Similar（Sima）的浓度，Sima是人类缺氧诱
导因子（HIFs）的同源分子，能够诱导Btl的表达，增加气管末端细胞中Btl的
浓度，促使细胞产生分枝。而在非气管细胞内，Sima能够诱导Bnl的表达，但也
可能有其它一些因子参与该过程。

研究人员指出，气管末端细胞在缺氧条件下通过自主反应，增加其表面受体Bt
l的浓度，能够使其对组织Bnl水平增加更加敏感，是缺氧诱导气管分枝的重要
步骤。此即“搜索模式”，和此前的“Bnl中心模式”一起更好解释了气管分枝
发生的机制，这一理论对哺乳动物的血管发生机制也有一定的启示。

该研究以封面论文形式发表于4月15日的《发育细胞》（Developmental Cell）
上。（科学网 穆宏平/编译）

推荐原始出处：

（Developmental Cell），Vol 14, 547-558, 15 April 2008，Lázaro Cent
anin, Pablo Wappner

Cell Autonomy of HIF Effects in Drosophila: Tracheal Cells Sense Hyp
oxia and Induce Terminal Branch Sprouting

Lázaro Centanin,1,4 Andrés Dekanty,1 Nuria Romero,1 Maximiliano Ir
isarri,1 Thomas A. Gorr,2,3 and Pablo Wappner1,3,

1 Instituto Leloir and FBMC, FCEyN-Universidad de Buenos Aires, CONI
CET, Patricias Argentinas 435, Buenos Aires 1405, Argentina

2 Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich C
enter for Integrative Human Physiology (ZIHP), University of Zurich,
Wintherthurerstrasse 260, CH-8057 Zurich, Switzerland

Summary

Drosophila tracheal terminal branches are plastic and have the capac
ity to sprout out projections toward oxygen-starved areas, in a proc
ess analogous to mammalian angiogenesis. This response involves the
upregulation of FGF/Branchless in hypoxic tissues, which binds its r
eceptor Breathless on tracheal cells. Here, we show that extra sprou
ting depends on the Hypoxia-Inducible Factor (HIF)-α homolog Sima a
nd on the HIF-prolyl hydroxylase Fatiga that operates as an oxygen s
ensor. In mild hypoxia, Sima accumulates in tracheal cells, where it
induces breathless, and this induction is sufficient to provoke tra
cheal extra sprouting. In nontracheal cells, Sima contributes to bra
nchless induction, whereas overexpression of Sima fails to attract t
erminal branch outgrowth, suggesting that HIF-independent components
are also required for full induction of the ligand. We propose that
the autonomous response to hypoxia that occurs in tracheal cells en
hances tracheal sensitivity to increasing Branchless levels, and tha
t this mechanism is a cardinal step in hypoxia-dependent tracheal sp
routing.