{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed a complex network of regulatory signals during organ development, in which secreted modulators of Wnt/β‐catenin signaling play pivotal roles. For instance, ectodysplasin‐A1 (Eda-A1) and canonical Wnt signals activate pathways that induce inhibitors such as Dickkopf 4 (DKK4), which in turn act to fine-tune placode formation in ectodermal appendages—including hairs, glands, teeth, and even specialized structures such as sweat glands and Meibomian glands. These reports demonstrate that DKK4 is expressed within developing placodes and is subject to feedback regulation by Wnt activity, ensuring proper patterning and morphogenesis during development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther investigations have extended the functional repertoire of DKK4 beyond ectodermal patterning. In congenital conditions such as anorectal malformations, rare copy number variations in DKK4 have been implicated in disrupting anorectal development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Additionally, studies in osteoblast-like cells show that DKK4 suppresses bone formation by inhibiting Wnt/β‐catenin activity, while in the context of hair follicle subtypes, differential regulation by DKK4 delineates pathways for primary (Eda-dependent) versus secondary (Eda-independent) hair development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In colorectal cancer, DKK4 has been found to be upregulated and to restrict metastatic behavior by engaging a negative feedback loop involving Wnt and AKT signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast to these multifaceted roles of DKK4 in developmental and oncogenic signaling, emerging evidence points to a distinct function for microRNA miR-4480. Specifically, serum profiling in patients with advanced breast cancer has identified miR-4480 as a promising biomarker capable of discriminating between patients with and without brain metastasis, achieving an area under the receiver operating characteristic curve of approximately 0.78. This finding underscores the potential of miR-4480 as a noninvasive diagnostic tool for predicting brain metastasis in breast cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hisham Bazzi, Katherine A Fantauzzo, Gavin D Richardson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Wnt inhibitor, Dickkopf 4, is induced by canonical Wnt signaling during ectodermal appendage morphogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2007.02.035"}], "href": "https://doi.org/10.1016/j.ydbio.2007.02.035"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17397822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17397822"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ingrid Fliniaux, Marja L Mikkola, Sylvie Lefebvre, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of dkk4 as a target of Eda-A1/Edar pathway reveals an unexpected role of ectodysplasin as inhibitor of Wnt signalling in ectodermal placodes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2008.04.023"}], "href": "https://doi.org/10.1016/j.ydbio.2008.04.023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18508042"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18508042"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Chang-Yi Cui, Makoto Kunisada, Yulan Piao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dkk4 and Eda regulate distinctive developmental mechanisms for subtypes of mouse hair."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0010009"}], "href": "https://doi.org/10.1371/journal.pone.0010009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20386733"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20386733"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Chang-Yi Cui, Mingzhu Yin, Jian Sima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Involvement of Wnt, Eda and Shh at defined stages of sweat gland development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.109231"}], "href": "https://doi.org/10.1242/dev.109231"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25249463"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25249463"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jian Sima, Yulan Piao, Yaohui Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.143909"}], "href": "https://doi.org/10.1242/dev.143909"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27864382"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27864382"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Emily H M Wong, Long Cui, Chun-Laam Ng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genome-wide copy number variation study in anorectal malformations."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/dds451"}], "href": "https://doi.org/10.1093/hmg/dds451"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23108157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23108157"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Shiro Hiramitsu, Masakazu Terauchi, Toshiro Kubota "}, {"type": "b", "children": [{"type": "t", "text": "The effects of Dickkopf-4 on the proliferation, differentiation, and apoptosis of osteoblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2013-1387"}], "href": "https://doi.org/10.1210/en.2013-1387"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24105477"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24105477"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Junrong Liang, Lina Sun, Yujun Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wnt signaling modulator DKK4 inhibits colorectal cancer metastasis through an AKT/Wnt/β-catenin negative feedback pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.jbc.2022.102545"}], "href": "https://doi.org/10.1016/j.jbc.2022.102545"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36181792"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36181792"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jun Sato, Akihiko Shimomura, Junpei Kawauchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Brain metastasis-related microRNAs in patients with advanced breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0221538"}], "href": "https://doi.org/10.1371/journal.pone.0221538"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31603918"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31603918"}]}]}]}