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DLK1

Official Full Name
delta like non-canonical Notch ligand 1
Organism
Homo sapiens
GeneID
8788
Background
This gene encodes a transmembrane protein that contains multiple epidermal growth factor repeats that functions as a regulator of cell growth. The encoded protein is involved in the differentiation of several cell types including adipocytes. This gene is located in a region of chromosome 14 frequently showing unparental disomy, and is imprinted and expressed from the paternal allele. A single nucleotide variant in this gene is associated with child and adolescent obesity and shows polar overdominance, where heterozygotes carrying an active paternal allele express the phenotype, while mutant homozygotes are normal. [provided by RefSeq, Nov 2015]
Synonyms
DLK; FA1; ZOG; pG2; DLK-1; PREF1; Delta1; Pref-1;
Protein Sequence
MTATEALLRVLLLLLAFGHSTYGAECFPACNPQNGFCEDDNVCRCQPGWQGPLCDQCVTSPGCLHGLCGEPGQCICTDGWDGELCDRDVRACSSAPCANNRTCVSLDDGLYECSCAPGYSGKDCQKKDGPCVINGSPCQHGGTCVDDEGRASHASCLCPPGFSGNFCEIVANSCTPNPCENDGVCTDIGGDFRCRCPAGFIDKTCSRPVTNCASSPCQNGGTCLQHTQVSYECLCKPEFTGLTCVKKRALSPQQVTRLPSGYGLAYRLTPGVHELPVQQPEHRILKVSMKELNKKTPLLTEGQAICFTILGVLTSLVVLGTVGIVFLNKCETWVSNLRYNHMLRKKKNLLLQYNSGEDLAVNIIFPEKIDMTTFSKEAGDEEI
Open
Disease
Motor neuron disease
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
0

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Detailed Information

A member of the Notch signaling system's non-canonical ligand family, the DLK1 gene (Delta-Like Homolog 1) produces a necessary transmembrane protein. The protein generated by the DLK1 gene features several epidermal growth factor (EGF) )---like repeat structures. Its primary goal is to regulate cell development and differentiation, so it is quite important for the differentiation processes of various cell types including adipocytes and neuroendocrine cells. Normal physiological conditions mainly confine the expression of DLK1 to embryonic development; expression in adults is limited to a small number of progenitor or precursor cells. This specific expression pattern suggests that tissue development and cell population stability depend on DLK1 somewhat heavily.

Usually defined by uniparental disomy, chromosome 14 hosts the DLK1 gene. Usually silent, the gene expresses itself solely from the paternal allele and exhibits an imprinting effect. Studies revealing a parent-of-origin impact have found that obesity in children and adolescents is closely associated with single nucleotide modifications in the DLK1 gene. Because of this genetic effect, heterozygous persons with the active paternal allele exhibit similar traits; homozygous people show no abnormalities.

DLK1 and Its Relationship with Precocious Puberty

Puberty, under control by a complex mix of environmental and genetic components, is set off by activation of the hypothalamic-pituitary-gonadal (HPG) axis. Recent studies reveal a substantial correlation between loss-of-function mutations in the DLK1 gene and central precocious puberty (CPP). CPP is marked by early sexual development; instances of this include breast development in girls before the age of eight and testicular growth in boys before the age of nine.

Originally reporting DLK1 loss-of-function mutations in 2017, researchers utilizing whole-genome sequencing discovered a deletion of around 14kb in the first exon and translation start site of the DLK1 gene in a Brazilian family. These people had an entire loss of DLK1 protein since their blood levels of it were undetectable. Exon sequencing also discovered several frameshift mutations in DLK1 that affect protein structure and function, hence generating metabolic abnormalities and early puberty.

Control of the notch signaling system is closely related to early puberty resulting from DLK1 mutations. Reducing the activation of Notch receptors helps the DLK1 protein control cell differentiation; mutations could thus affect the normal control of GnRH production. Moreover, altered lipid metabolism and aberrant DLK1 expression could increase metabolic issues in patients experiencing precocious puberty.

DLK1 Expression and Its Role in Cancer

Numerous malignancies, including kidney cancer, neuroendocrine tumors, liver cancer, and lung cancer, have shown aberrant expression of DLK1. Expression of DLK1 is often linked in various tumors to tumor aggressiveness and poor prognosis.

Figure 1 illustrates DLK1 elevated expression in cancer, outlines its two isoforms, their interaction pathways, and possible signaling modes, and proposes a hypothesis on DLK1 oncogenic effects.Figure 1. The role of DLK1 in cancer. (Pittaway JFH, et al., 2021)

Role of PSD-95 in Neuropsychiatric Disorders

Liver Cancer: Particularly hepatoblastoma, DLK1 is regarded as a marker of hepatic progenitor cells in liver cancer; high expression is a molecular characteristic of hepatoblastoma. Research indicates that epigenetic changes in the 14q32 genomic area—such as hypomethylation of CpG sites or hypermethylation of imprinting regulatory areas—may control DLK1 expression. These systems may cause unusually high DLK1 expression, hence fostering tumor cell proliferation and differentiation abnormalities.

Lung Cancer: Both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) have also been extensively documented in high-frequency expression of DLK1. Suggesting its possible oncogenic function, DLK1 mRNA levels in 37% of tumor samples in NSCLC are much greater than in surrounding normal tissues. Hypomethylation of the DLK1-DIO3 area is thought to be one possible explanation for its high expression, even if particular epigenetic pathways are yet unknown.

Neuroendocrine Tumors: High DLK1 expression is also observed in various neuroendocrine tumors, such as adrenocortical carcinoma, pheochromocytoma, and pancreatic neuroendocrine tumors. High DLK1 expression is linked in adrenocortical carcinoma to a higher risk of tumor recurrence and worse survival results. Studies have also shown that using the Notch signaling system, DLK1 expression levels might control the malignant activity of tumor cells.

Other Tumors: In acute myeloid leukemia (AML), DLK1 expression levels vary among patients. Certain studies propose that aberrant DLK1 expression could be connected to its loss of imprinting (LOI), an epigenetic modification that might modify the gene-regulating ability of DLK1. Moreover, aberrant DLK1 expression in some kidney malignancies and gastrointestinal stromal tumors (GIST) suggests its special function in carcinogenesis among several tissues.

Functions and Molecular Mechanisms of DLK1

DLK1 plays an important role in normal physiology by regulating cell differentiation, tissue development, and growth. During embryonic stages, high expression of DLK1 promotes organ formation, while in adults, its expression is restricted to limited progenitor cells, likely aiding in maintaining tissue homeostasis. However, in tumor cells, abnormally high DLK1 expression may indicate reactivation of a dedifferentiated cellular state, leading to uncontrolled proliferation and differentiation disorders.

The function of DLK1 primarily depends on the Notch signaling pathway. Research shows that DLK1 can inhibit the activity of Notch receptors, thereby regulating cell fate decisions. However, abnormal expression of DLK1 may promote oncogenic behaviors in tumor cells through the Notch signaling pathway, such as epithelial-mesenchymal transition (EMT), angiogenesis, and cell cycle dysregulation.

Genetic Imprinting and Association with Hereditary Diseases

Genetic imprinting controls the expression of the DLK1 gene, so it has special relevance in hereditary disorders. Temple syndrome brought on by mother uniparental disomy, for example, shows low birth weight, growth retardation, and metabolic problems, may be linked to low levels of DLK1 expression. Further underscoring DLK1's crucial involvement in controlling growth and metabolism, in individuals with central precocious puberty, DLK1 loss-of-function mutations commonly accompany insulin resistance and lipid metabolic abnormalities.

References:

  1. Macedo DB, Kaiser UB. DLK1, Notch Signaling and the Timing of Puberty. Semin Reprod Med. 2019 Jul;37(4):174-181.
  2. Pittaway JFH, Lipsos C, et al. The role of delta-like non-canonical Notch ligand 1 (DLK1) in cancer. Endocr Relat Cancer. 2021 Oct 15;28(12):R271-R287.
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