Brancaccio Anna, Minichiello Annunziata, Grachtchouk Marina, Antonini Dario, Sheng Hong, Parlato Rosanna, Dathan Nina, Dlugosz Andrzej A, Missero Caterina
Telethon Institute of Genetics and Medicine (TIGEM), via Pietro Castellino 111, 80131 Napoli, Italy.
Hum Mol Genet. 2004 Nov 1;13(21):2595-606. doi: 10.1093/hmg/ddh292. Epub 2004 Sep 14.
The forkhead transcription factor FOXE1 is mutated in patients with Bamforth-Lazarus syndrome that exhibit hair follicle defects, suggesting a possible role for Foxe1 in hair follicle morphogenesis. Here, we report that Foxe1 is specifically expressed in the lower undifferentiated compartment of the hair follicle, at a time and site that parallel activation of the Shh signaling pathway. The Foxe1 protein is also expressed in human and mouse basal cell carcinoma in which hedgehog signaling is constitutively activated, whereas it is undetectable in normal epidermis and squamous cell carcinoma. Moreover, expression of a dominant-negative form of Gli2 in skin results in complete suppression of Foxe1 expression in the hair follicle, whereas transcriptionally active Gli2 stimulates activity of the Foxe1 promoter. Foxe1-null skin displays aberrant hair formation with the production of thinner and curly pelage hairs. Although the hair follicle internal structure is conserved and several lineage markers are properly expressed, the orderly downgrowth of follicles is strikingly disrupted, causing disorientation, misalignment and aberrantly shaped of hair follicles. Our findings provide a strong indication that the defect in Bamforth-Lazarus syndrome is due to altered FOXE1 function in the hair follicle, and is independent of systemic defects present in affected individuals. In addition, we establish Foxe1 as a downstream target of the Shh/Gli pathway in hair follicle morphogenesis, and as a crucial player for correct hair follicle orientation into the dermis and subcutis.
叉头转录因子FOXE1在患有表现出发毛囊缺陷的班福思-拉扎勒斯综合征的患者中发生突变，这表明Foxe1在毛囊形态发生中可能发挥作用。在此，我们报告Foxe1在毛囊的较低未分化区室中特异性表达，其时间和位点与Shh信号通路的激活平行。Foxe1蛋白也在刺猬信号通路持续激活的人类和小鼠基底细胞癌中表达，而在正常表皮和鳞状细胞癌中无法检测到。此外，在皮肤中表达显性负性形式的Gli2会导致毛囊中Foxe1表达完全受到抑制，而转录活性的Gli2会刺激Foxe1启动子的活性。Foxe1基因敲除的皮肤表现出毛发形成异常，产生更细且卷曲的被毛。尽管毛囊内部结构得以保留且一些谱系标记物表达正常，但毛囊的有序向下生长受到显著破坏，导致毛囊方向紊乱、排列不齐和形状异常。我们的研究结果有力地表明，班福思-拉扎勒斯综合征的缺陷是由于毛囊中FOXE1功能改变所致，且与受影响个体中存在的全身缺陷无关。此外，我们确定Foxe1是毛囊形态发生中Shh/Gli通路的下游靶点，也是毛囊正确定向到真皮和皮下组织的关键因素。
