Dickkopf-related protein 1 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''DKK1''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

Function

This gene encodes a protein that is a member of the dickkopf family. It is a secreted protein with two

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

rich regions and is involved in embryonic development through its inhibition of the

Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...

. Dickkopf WNT signaling pathway inhibitor 1 (Dkk1) is a protein-coding gene that acts from the anterior visceral endoderm. The dickkopf protein encoded by DKK1 is an antagonist of the Wnt/β-catenin signalling pathway that acts by isolating the LRP6 co-receptor so that it cannot aid in activating the WNT signaling pathway. This inhibition plays a key role in heart, head and forelimb development during anterior

morphogenesis Morphogenesis (from the Greek ''morphê'' shape and ''genesis'' creation, literally "the generation of form") is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of deve ...

of the embryo.

Interactions

DKK1 has been shown to interact with LRP6 and is a high affinity ligand of Kremen proteins.

Clinical significance

Elevated levels of DKK1 in bone marrow, plasma and peripheral blood are associated with the presence of osteolytic bone lesions in patients with

multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...

. Due to the role of DKK1 in inflammation induced bone loss DKK1 is under investigation as target for therapeutic strategies in medicine and dentistry.

Animal studies

Scientists have created a DKK1 knockout model in mice that revealed the effects of this gene. All mice that were homozygous for the DKK1 knockout were dead at birth due to defects in the cranium and structures formed by the neural crest, such as failed development of eyes, olfactory placodes, frontonasal mass and mandibular processes, as well as incomplete development of the forebrain and midbrain and fusion of the digits of the forelimb. This evidence supports the idea that inhibition of the Wnt signaling pathway by DKK1 is crucial to proper cranial development.

In vitro studies

DKK1 is one of the most upregulated genes in androgen-potentiated balding, with DKK-1

messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...

upregulated a few hours after DHT treatment of hair follicles at the dermal papilla ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

''. Neutralizing antibody against DKK-1 reversed DHT effects on outer root sheath keratinocytes. DKK-1 expression is attenuated by L-threonate ''in vitro'', with the latter a metabolite of

ascorbate Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables. It is also a generic prescription medication and in some countries is sold as a non-prescription die ...

DKK1 and Alzheimer's

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

occurs due to the overproduction of

amyloid beta Amyloid beta (Aβ, Abeta or beta-amyloid) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor prot ...

that will cluster together to form

amyloid plaques Amyloid plaques (also known as neuritic plaques, amyloid beta plaques or senile plaques) are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degeneration (medical), Degenerative neuronal ...

between neurons in the brain and disrupt cell function. In addition, there is an accumulation of neurofibrillary tangles of hyperphosphorylated tau inside the neuron. The Wnt signaling pathway is crucial for brain development processes, which include neuron proliferation and differentiation as well as neuroblast migration and axon guidance. Downregulation of this signaling has been shown in those with Alzheimer's as a result of high levels of DKK1. Because of the hyperphosphorylation induced by DKK1, tau cannot interact with neuronal microtubules consequently compromising

axonal transport Axonal transport, also called axoplasmic transport or axoplasmic flow, is a cellular process responsible for movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles to and from a neuron's cell body, through the cytopla ...

resulting in synaptic loss and neuronal apoptosis. Because of its antagonistic effects on the Wnt signaling pathway, it is believed that DKK1 is a common marker for neuronal death in neurodegenerative diseases like Alzheimer's.