Forkhead box D1 is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

that in humans is encoded by the FOXD1

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. Forkhead d1 is a kidney expressed transcription factor maps at the chromosome 5 at position 5q12—q13, identified in ''

Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many speci ...

forkhead'' protein and mammalian HNF3 transcription factor. The name of was derived from two spiked head structures in the embryos of ''Drosophila forkhead mutant''. It belong to

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

family that displays remarkable functional diversity and involved in a wide variety of biological processes. The most commonly used synonyms for Forkhead D1 are, FOX D1, FREAC-4 and BF2.

Structure

The Forkhead domain in FOXD1 is distinctive from other members of the same family except, FREAC-9 also known as FOXD2. The amino acid sequence of the DNA binding forkhead motif of FREAC-4 is similar to FREAC-9, except 12 substitution are present at the nucleotide level. The

DNA binding domain A DNA-binding domain (DBD) is an independently folded protein domain that contains at least one structural motif that recognizes double- or single-stranded DNA. A DBD can recognize a specific DNA sequence (a recognition sequence) or have a genera ...

is winged helix consist of around 100 amino acids, has four helices and two stranded beta-sheets, the sequence extends from nucleotide 2521 to 4792. This gene is estimated to be approximately 2.5 kilo base pairs and, most likely introns less. The motif at NH2 terminal part is highly acidic and rich in

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

s at COOH terminal, this is similar to the transcription factor UBF and WT-1. It is indicated in cotransfection experiments, that the tumour suppressor gene p53 and WT-1 are potential regulators of FREAC-4. FOXD1 is expressed by two kidney derived cell line COS 7 and 293 cells. It also has high degree of sequence similarity with FOXD1 found by cloned mouse

cDNA In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA (e.g., messenger RNA (mRNA) or microRNA (miRNA)) template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to express a sp ...

Functions

Studies of the orthologous mouse protein indicate that it functions in kidney development by promoting

nephron The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ...

progenitor differentiation, and it also functions in the development of the retina and

optic chiasm In neuroanatomy, the optic chiasm, or optic chiasma (; , ), is the part of the brain where the optic nerves cross. It is located at the bottom of the brain immediately inferior to the hypothalamus. The optic chiasm is found in all vertebrat ...

. It may also regulate inflammatory reactions and prevent

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

. FOXD1 and

stromal cell Stromal cells, or mesenchymal stromal cells, are differentiating cells found in abundance within bone marrow but can also be seen all around the body. Stromal cells can become connective tissue cells of any organ, for example in the uterine mucosa ...

have essential function during kidney

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 ...

. Placental growth factor (PIGF) is a direct and physiologically relevant transcriptional target of FOXD1 and hence, it is co-expressed with FOXD1 for the development of renal stroma. Two isoforms of PIGF, PIGF1 and PIGF 2 are found in human. In an experiment, three genes were found to be identified by induced FOXD1 in Northern blotting. First, PIGF initiates stromal signal that regulate epithelial differentiation which functions as a growth factor in reactive

angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splittin ...

during wound healing and

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnor ...

. Second, heparin binding epidermal growth factor and lastly, the bHLH protein G0S8. Foxd1 is also required for proper formation of

. During the formation of optic chiasm, Foxd1 is expressed in VT retina, as well as in the ventral diencephalon for retinal development and chiasm morphogenesis. During visual system development,

retinal ganglion cell A retinal ganglion cell (RGC) is a type of neuron located near the inner surface (the ganglion cell layer) of the retina of the eye. It receives visual information from photoreceptors via two intermediate neuron types: bipolar cells and reti ...

(RGC) axons leave the retina via optic disc until they reach the optic chiasm. Foxg1 and Foxd1 are expressed in adjacent domains in the neural tube at the time, the optical vesicle evaginates. Misexpression of Foxd1 and Foxg1 in chick retina creates projection error in retinal axons along the antiposterior axis in the

tectum The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal ( alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...

and, it also plays a role in the specification of contralateral RGCs. It is determined that Foxd1 is essential for the correct formation of optic chiasm. FOX D1 expressed and function in

Glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

cell behaviour, it upregulates and directly correlates with the glioma grade. Delayed expression of FOX D1 causes decreased glioma cell growth and reduce cell migration. There is a high probability that FOXD1 can serve as a novel regulator of glioblastoma cell behaviour that could be used as a novel target for gene targeted therapies. In mice, Foxd1 is expressed in the

mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood or bone. The interactions between mesenchyme and epithelium help to form nearly every ...

surrounding the pituitary gland, which is an essential source for signaling factors that regulate pituitary

organogenesis Organogenesis is the phase of embryonic development that starts at the end of gastrulation and continues until birth. During organogenesis, the three germ layers formed from gastrulation (the ectoderm, endoderm, and mesoderm) form the internal org ...

. It suggests that Foxd1 is indirectly involved in Lhb expression and

cartilage Cartilage is a resilient and smooth type of connective tissue. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck ...

formation.

Disease

The chromosomal duplication in the region 5q12-13 of chromosome 5 causes dysplastic kidneys and mental disorders which is relevant to tissue distribution o FREAC-4 mRNA.

References

{{Transcription factors, g3 Forkhead transcription factors