Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), Montreal, QC, Canada.
Neural Dev. 2010 Nov 2;5:28. doi: 10.1186/1749-8104-5-28.
The Hedgehog (Hh) signaling pathway is important for the development of a variety of tissues in both vertebrates and invertebrates. For example, in developing nervous systems Hh signaling is required for the normal differentiation of neural progenitors into mature neurons. The molecular signaling mechanism underlying the function of Hh is not fully understood. In Drosophila, Ihog (Interference hedgehog) and Boi (Brother of Ihog) are related transmembrane proteins of the immunoglobulin superfamily (IgSF) with orthologs in vertebrates. Members of this IgSF subfamily have been shown to bind Hh and promote pathway activation but their exact role in the Hh signaling pathway has remained elusive. To better understand this role in vivo, we generated loss-of-function mutations of the ihog and boi genes, and investigated their effects in developing eye and wing imaginal discs.
While mutation of either ihog or boi alone had no discernible effect on imaginal tissues, cells in the developing eye disc that were mutant for both ihog and boi failed to activate the Hh pathway, causing severe disruption of photoreceptor differentiation in the retina. In the anterior compartment of the developing wing disc, where different concentrations of the Hh morphogen elicit distinct cellular responses, cells mutant for both ihog and boi failed to activate responses at either high or low thresholds of Hh signaling. They also lost their affinity for neighboring cells and aberrantly sorted out from the anterior compartment of the wing disc into posterior territory. We found that ihog and boi are required for the accumulation of the essential Hh signaling mediator Smoothened (Smo) in Hh-responsive cells, providing evidence that Ihog and Boi act upstream of Smo in the Hh signaling pathway.
The consequences of boi;ihog mutations for eye development, neural differentiation and wing patterning phenocopy those of smo mutations and uncover an essential role for Ihog and Boi in the Hh signaling pathway.
Hedgehog（Hh）信号通路对脊椎动物和无脊椎动物的各种组织的发育都很重要。例如，在发育中的神经系统中，Hh 信号对于神经祖细胞正常分化为成熟神经元是必需的。Hh 功能的分子信号机制尚未完全了解。在果蝇中，Ihog（干扰 Hedgehog）和 Boi（Ihog 的兄弟）是免疫球蛋白超家族（IgSF）的相关跨膜蛋白，在脊椎动物中有同源物。该 IgSF 亚家族的成员已被证明可以结合 Hh 并促进途径激活，但它们在 Hh 信号通路中的确切作用仍不清楚。为了更好地在体内理解这一作用，我们生成了 ihog 和 boi 基因的功能丧失突变，并研究了它们在发育中的眼和翅 imaginal 盘上的影响。
虽然单独突变 ihog 或 boi 对 imaginal 组织没有明显影响，但突变了 both ihog 和 boi 的发育中的眼盘细胞未能激活 Hh 途径，导致视网膜中光感受器分化严重中断。在发育中的翅盘的前区，不同浓度的 Hh 形态发生素引发不同的细胞反应，突变了 both ihog 和 boi 的细胞未能在 Hh 信号的高或低阈值下激活反应。它们也失去了与邻近细胞的亲和力，并从翅盘的前区异常分拣到后区。我们发现 ihog 和 boi 是必需的，以在 Hh 反应细胞中积累必需的 Hh 信号介质 Smoothened（Smo），这提供了 Ihog 和 Boi 在 Hh 信号通路中 Smo 上游起作用的证据。
boi;ihog 突变对眼睛发育、神经分化和翅膀模式形成的影响与 smo 突变相似，并揭示了 Ihog 和 Boi 在 Hh 信号通路中的重要作用。
