FAT3

Official Full Name

FAT atypical cadherin 3

Organism

Homo sapiens

GeneID

120114

Background

Predicted to enable calcium ion binding activity. Predicted to be involved in cell-cell adhesion. Predicted to act upstream of or within generation of neurons; negative regulation of dendrite development; and retina layer formation. Predicted to be located in dendrite and plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

hFat3; CDHF15; CDHR10;

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Detailed Information

Fat-related genes were first identified by Mahoney in Drosophila, which encodes a large transmembrane protein with 34 cadherin repeats, 4 epidermal cell growth factor (EGF)-like domains, and 2 laminin C-like domains. FAT3 is one of four fat-related genes, FAT1-FAT4, that are known to be expressed in large quantities in the mammalian brain. FAT3 can induce abnormal actin filaments orientation in the ovaries of drosophila. In the central nervous system, FAT3 is mainly expressed in neurons and responsible for regulating the morphology of retinal neurons. In the retina, a single dendrite is projected to the inner plexiform layer (IPL) which is used to separate the cell body of the inner nuclear layer (INL) from the cell body of the ganglion cell layer. In fat3 mutant mice, a second projection away from IPL formed in many amacrine cells and two ectopic synaptic layers formed in the mature retina. Although it is dramatic, it is still unclear how fat3 usually prevents amacrine cells from expanding additional dendrites. On the contrary, fat3 protein is asymmetrically located in the process of amacrine cells in IPL which is opposite to the position of external nerve process formation. This increases the possibility that, like more familiar polar proteins, fat3 may transmit a local signal and affect the cytoskeleton of the whole neuron. Recently, more and more experimental studies have been proved that FAT family members are closely related to the occurrence, development, and prognosis of tumors, which has attracted people's attention.

FAT3 Associated with Esophageal Cancer

Esophageal cancer (ESCA), as a universal malignant tumor, includes esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EADC). ESCA is normally identified by progressive dysphagia, and it can be identified only when most patients have entered the advanced stage. Although some progress in ESCA surgical techniques has been made, such as chemotherapy, radiotherapy protocols, and perioperative management, only 19% of patients with ESCA survived according to the 5-year survival rate, which results in a serious threat to human health. Therefore, the exploration of the mutated genes associated with esophageal cancer is essential to prevent ESCA. The mutated genes in ESCA and the advantages of FAT3 regarded as a potential prognostic marker were fully explored by Hu’s group. FAT3 has been demonstrated as a high-frequency mutation that exists in both the cancer genome atlas (TCGA) and international cancer genome consortium (ICGC) samples. Furthermore, the TMB of FAT3 mutant in ESCA patients was significantly higher than that of wild-type (P < 0.05). Meanwhile, the prognosis of ESCA patients with FAT3 mutants was significantly worse (P<0.05), and the mutation status of FAT3 might be an independent factor affecting the prognosis of ESCA patients (HR: 1.262-5.922, P=0.011).

FAT3 as a Novel Mediator for Morphological Changes of Microglia

Microglia, as one of the resident macrophages, is essential for brain development and homeostasis. Microglia morphology changes dynamically in the postnatal stage, leading to synaptogenesis and synaptic regulation. In addition, it is well known that the shape of microglia will also change due to debris, apoptotic cells, and pathogens. Although morphological changes are essential for obtaining microglia function, the exact mechanism controlling its morphology has been not fully understood. Fat3 was reported to regulate the morphology of microglia, BV2, by Okajima et al. The shape of BV2 was found to be elongated in the medium with high nutrition. Furthermore, the expression of fat3 in microarray analysis was demonstrated to be induced in the high nutrient medium. What’s more, it is found that the expression of fat3 was promoted by the purinergic analogue, hypoxanthine in BV2 and mouse primary cells.

FAT3 Figure 1. A model describing the functions of FAT3 in microglia. FAT3 expression is induced by hypoxanthine in microglia. FAT3 localized on the tip of the microglial process may stabilize actin reorganization in concert with a humoral factor. (Okajima et al. 2020)

References:

Krol A, Henle S J, Goodrich L V. Fat3 and Ena/VASP proteins influence the emergence of asymmetric cell morphology in the developing retina[J]. Development, 2016, 143(12): 2172-2182.
Guo Z, Yan X, Song C, et al. FAT3 Mutation Is Associated With Tumor Mutation Burden and Poor Prognosis in Esophageal Cancer[J]. Frontiers in Oncology, 2021, 11: 378.
Okajima T, Gu Y, Teruya R, et al. Atypical cadherin FAT3 is a novel mediator for morphological changes of microglia[J]. Eneuro, 2020, 7(6).

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