Liu Ning-Ai, Ren Meina, Song Jianbo, Ríos Yesenia, Wawrowsky Kolja, Ben-Shlomo Anat, Lin Shuo, Melmed Shlomo
Department of Medicine, Cedars-Sinai Research Institute, University of California Los Angeles, Los Angeles, California 90048, USA.
Dev Biol. 2008 Jul 15;319(2):192-200. doi: 10.1016/j.ydbio.2008.03.039. Epub 2008 Apr 9.
The anterior pituitary gland (adenohypophysis) comprises anterior and intermediate lobes (the pars distalis and pars intermedia) arising from placodal ectoderm at the anterior neural ridge. Signaling molecules including SHH, FGF, WNT, BMP and Notch are involved in regulating primordial pituitary proliferation and lineage determination. However, morphogenic events and molecular mechanisms governing anterior and intermediate lobe specification are not clear. Pituitary expression of proopiomelanocortin (POMC), the common precursor for adrenocorticotropin (ACTH) of pars distalis corticotropes and alpha-melanocyte-stimulating hormone (alpha-MSH) of pars intermedia melanotropes, provides a unique marker for anterior and intermediate lobe morphogenesis. We performed time-lapse confocal microscopy lineage tracing in live zebrafish embryos expressing GFP driven by the pomc promoter and show distinct migration pathways of POMC cells destined to the anterior and intermediate lobes. Using morpholino oligonucleotides, we show that hypomorphic FGF3 down-regulation induces specific defects of pars intermedia POMC cells while pomc, growth hormone and prolactin expression remain intact in the pars distalis. This lineage-specific process is independent of the FGF3 effect on early pituitary specifying transcription factors as indicated by normal Lim3 and Pit1 expression in hypomorphic FGF3 morphants. These findings suggest that the FGF3 signal, in addition to its previously described role of regulating progenitor proliferation and survival, delineates the melanotrope and corticotrope lineage boundary, contributing to establishment of the pituitary pars distalis and pars intermedia.
腺垂体（垂体前叶）由起源于前神经嵴的基板外胚层的前叶和中间叶（远侧部和中间部）组成。包括音猬因子（SHH）、成纤维细胞生长因子（FGF）、Wnt信号蛋白、骨形态发生蛋白（BMP）和Notch在内的信号分子参与调节原始垂体的增殖和谱系确定。然而，控制前叶和中间叶特化的形态发生事件和分子机制尚不清楚。阿黑皮素原（POMC）在垂体中的表达是前叶和中间叶形态发生的独特标志物，POMC是远侧部促肾上腺皮质激素细胞的促肾上腺皮质激素（ACTH）和中间部促黑素细胞的α-促黑素细胞激素（α-MSH）的共同前体。我们在由pomc启动子驱动表达绿色荧光蛋白（GFP）的活斑马鱼胚胎中进行了延时共聚焦显微镜谱系追踪，结果显示POMC细胞向垂体前叶和中间叶迁移的途径不同。使用吗啉代寡核苷酸，我们发现低表达FGF3会导致中间部POMC细胞出现特定缺陷，而远侧部的pomc、生长激素和催乳素表达保持完整。如低表达FGF3的吗啉代处理胚胎中Lim3和Pit1表达正常所示，这一谱系特异性过程独立于FGF3对早期垂体特异性转录因子的影响。这些发现表明，FGF3信号除了其先前描述的调节祖细胞增殖和存活的作用外，还划定了促黑素细胞和促肾上腺皮质激素细胞谱系边界，有助于垂体远侧部和中间部的形成。
