Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania.
Division of Experimental Pathology, Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Am J Pathol. 2023 May;193(5):558-566. doi: 10.1016/j.ajpath.2023.01.011. Epub 2023 Feb 10.
Hepatic zonation is critical for most metabolic functions in liver. Wnt signaling plays an important role in establishing and maintaining liver zonation. Yet, the anatomic expression of Wnt signaling components, especially all 10 Frizzled (Fzd) receptors, has not been characterized in adult liver. To address this, the spatial expression of Fzd receptors was quantitatively mapped in adult mouse liver via multiplex fluorescent in situ hybridization. Although all 10 Fzd receptors were expressed within a metabolic unit, Fzd receptors 1, 4, and 6 were the highest expressed. Although most Wnt signaling occurs in zone 3, expression of most Fzd receptors was not zonated. In contrast, Fzd receptor 6 was preferentially expressed in zone 1. Wnt2 and Wnt9b expression was highly zonated and primarily found in zone 3. Therefore, the current results suggest that zonated Wnt/β-catenin signaling at baseline occurs primarily due to Wnt2 and Wnt9b rather than zonation of Fzd mRNA expression. Finally, the study showed that Fzd receptors and Wnts are not uniformly expressed by all hepatic cell types. Instead, there is broad distribution among both hepatocytes and nonparenchymal cells, including endothelial cells. Overall, this establishment of a definitive mRNA expression atlas, especially of Fzd receptors, opens the door to future functional characterization in healthy and diseased liver states.
肝分区对于肝脏的大多数代谢功能至关重要。Wnt 信号在建立和维持肝分区中起着重要作用。然而,Wnt 信号成分的解剖表达,特别是所有 10 个卷曲(Fzd)受体,尚未在成年肝脏中得到描述。为了解决这个问题,通过多重荧光原位杂交定量绘制了成年小鼠肝脏中 Fzd 受体的空间表达。尽管所有 10 个 Fzd 受体都在一个代谢单元内表达,但 Fzd 受体 1、4 和 6 的表达水平最高。尽管大多数 Wnt 信号发生在区 3,但大多数 Fzd 受体的表达没有分区。相比之下,Fzd 受体 6 优先在区 1 表达。Wnt2 和 Wnt9b 的表达高度分区,主要存在于区 3。因此,目前的结果表明,基线时分区的 Wnt/β-catenin 信号主要是由于 Wnt2 和 Wnt9b 而不是 Fzd mRNA 表达的分区。最后,该研究表明,Fzd 受体和 Wnts 不是由所有肝实质细胞类型均匀表达的。相反,它们在肝细胞和非实质细胞(包括内皮细胞)中广泛分布。总体而言,这种明确的 mRNA 表达图谱的建立,特别是 Fzd 受体的建立,为未来在健康和疾病肝脏状态下的功能特征开辟了道路。