PDF(Pubmed)
Abstract：
LIM homeobox 4 (LHX4) is a transcription factor crucial for anterior pituitary (AP) development. Patients with LHX4 mutation suffer from combined pituitary hormone deficiency (CPHD), short statures, reproductive and metabolic disorders and lethality in some cases. Lhx4-knockout (KO) mice fail to develop a normal AP and die shortly after birth. Here, we characterize a zebrafish lhx4-KO model to further investigate the importance of LHX4 in pituitary gland development and regulation. At the embryonic and larval stages, these fish express lower levels of tshb mRNA compared with their wildtype siblings. In adult lhx4-KO fish, the expressions of pituitary hormone-encoding transcripts, including growth hormone (gh), thyroid stimulating hormone (tshb), proopiomelanocortin (pomca) and follicle stimulating hormone (fshb), are reduced, the pomca promoter-driven expression in corticotrophs is dampened and luteinizing hormone (lhb)-producing gonadotrophs are severely depleted. In contrast to Lhx4-KO mice, Lhx4-deficient fish survive to adulthood, but with a reduced body size. Importantly, lhx4-KO males reach sexual maturity and are reproductively competent, whereas the females remain infertile with undeveloped ovaries. These phenotypes, which are reminiscent of those observed in CPHD patients, along with the advantages of the zebrafish for developmental genetics research, make this lhx4-KO fish an ideal vertebrate model to study the outcomes of LHX4 mutation.
摘要：
LIM同源异型盒4（LHX4）是一种对垂体前叶（AP）发育至关重要的转录因子。LHX4突变患者患有联合垂体激素缺乏症（CPHD），身材矮小，生殖和代谢紊乱以及某些情况下的致死性。Lhx4敲除(KO)小鼠不能形成正常的AP并在出生后不久死亡。这里,我们描述了斑马鱼lhx4-KO模型，以进一步研究LHX4在垂体发育和调节中的重要性。在胚胎和幼虫阶段，与它们的野生型同胞相比，这些鱼表达的tshbmRNA水平较低。在成年lhx4-KO鱼中，垂体激素编码转录物的表达，包括生长激素（gh），促甲状腺激素(tshb),proopiomelanocortin（pomca）和卵泡刺激素（fshb），减少了，在促肾上腺皮质激素中pomca启动子驱动的表达被抑制，产生黄体生成素（lhb）的促性腺激素被严重耗尽。与Lhx4-KO小鼠相反，缺乏Lhx4的鱼存活到成年，但是身体尺寸缩小了。重要的是,lhx4-KO男性达到性成熟，有生殖能力，而雌性卵巢不发育，仍然不育。这些表型，这让人想起在CPHD患者中观察到的那些，以及斑马鱼在发育遗传学研究中的优势，使这种lhx4-KO鱼成为研究LHX4突变结果的理想脊椎动物模型。
