GDF Family

Overview

Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development. They are produced as inactive preproproteins which are then cleaved and assembled into active secreted homodimers. GDF dimers are disulfide-linked with the exception of GDF-3 and GDF-9. GDF proteins are important during embryonic development, particularly in the skeletal, nervous, and muscular systems.

Members of GDF family

Table 1. GDF family related products

• GDF1

Growth differentiation factor 1 (GDF1) is a protein that in humans is encoded by the GDF1 gene. GDF1 belongs to the transforming growth factor beta superfamily that has a role in left-right patterning and mesoderm induction during embryonic development. It is found in the brain, spinal cord and peripheral nerves of embryos.

• GDF2

Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene. GDF2 belongs to the transforming growth factor beta superfamily. GDF2 contains an N-terminal TGF-beta-like pro-peptide (prodomain) (residues 56–257) and a C-terminal transforming growth factor beta superfamily domain (325–428). GDF2 is secreted as a pro-complex consisting of the BMP9 growth factor dimer non-covalently bound to two BMP9 prodomain molecules in an open-armed conformation.

• GDF3

Growth differentiation factor 3 (GDF3), also known as Vg-related gene 2 (Vgr-2) is protein that in humans is encoded by the GDF3 gene. GDF3 belongs to the transforming growth factor beta (TGF-β) superfamily. It has high similarity to other TGF-β superfamily members including Vg1 (found in frogs) and GDF1. GDF-3 transcripts were detected primarily in adult bone marrow, spleen, thymus, and adipose tissue.

• GDF5

Growth differentiation factor 5 is a protein that in humans is encoded by the GDF5 gene. GDF5 is a protein belonging to the transforming growth factor beta superfamily that is expressed in the developing central nervous system, and has a role in skeletal and joint development. It also increases the survival of neurones that respond to the neurotransmitter dopamine, and is a potential therapeutic molecule associated with Parkinson's disease.

Figure 1. Structure of the GDF5 protein.

• GDF6

Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene. GDF6 may regulate patterning of the ectoderm by interacting with bone morphogenetic proteins, and control eye development. It is a regulatory protein associated with growth and differentiation of developing embryos. GDF6 has been shown to play an important role in the patterning of the epidermis and bone and joint formation. GDF6 induces genes related to the development of the epidermis and can bind directly to noggin, a gene that controls neural development, to block its effect.

• GDF9

Growth differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene. It is an oocyte derived growth factor in the transforming growth factor β (TGF-β) superfamily. Growth factors synthesized by ovarian somatic cells directly affect oocyte growth and function. GDF9 is expressed in oocytes and is thought to be required for ovarian folliculogenesis. It is highly expressed in the oocyte and has a pivotal influence on the surrounding somatic cells, particularly granulosa, cumulus and theca cells. Paracrine interactions between the developing oocyte and its surrounding follicular cells are essential for the correct progression of both the follicle and the oocyte. GDF9 is essential for the overall process of folliculogenesis, oogenesis and ovulation and thus plays a major role in female fertility.

• GDF10

Growth differentiation factor 10 (GDF10) also known as bone morphogenetic protein 3B (BMP-3B) is a protein that in humans is encoded by the GDF10 gene. GDF10 belongs to the transforming growth factor beta superfamily that is closely related to bone morphogenetic protein-3 (BMP3). It plays a role in head formation and may have multiple roles in skeletal morphogenesis. GDF10 is also known as BMP-3b, with GDF10 and BMP3 regarded as a separate subgroup within the TGF-beta superfamily. In mice, GDF10 mRNA is abundant in the brain, inner ear, uterus, prostate, neural tissues, blood vessels and adipose tissue with low expression in spleen and liver. It is also present in bone of both adults and neonatal mice. Human GDF10 mRNA is found in the cochlea and lung of foetuses, and in testis, retina, pineal gland, and other neural tissues of adults.

• GDF11

Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the growth differentiation factor 11 gene. It acts as a cytokine. GDF11 is a myostatin(GDF8)-homologous protein that acts as an inhibitor of nerve tissue growth. GDF11 has been shown to suppress neurogenesis through a pathway similar to that of myostatin, including stopping the progenitor cell-cycle during G-phase. The similarities between GDF11 and myostatin imply a likelihood that the same regulatory mechanisms are used to control tissue size during both muscular and neural development.

• GDF15

Growth differentiation factor 15 (GDF15) was first identified as Macrophage inhibitory cytokine-1 or MIC-1. It is produced by late-stage erythroid precursors in the bone marrow. Under normal conditions, GDF-15 is expressed in low concentrations in most organs and upregulated because of injury of organs such as liver, kidney, heart and lung. The function of GDF-15 is not fully cleared but seems to have a role in regulating inflammatory pathways and to be involved in regulating apoptosis, cell repair and cell growth, which are biological processes observed in cardiovascular and neoplastic disorders. GDF-15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer.

Cellular functions

GDF2 has a role in inducing and maintaining the ability of embryonic basal forebrain cholinergic neurons (BFCNs) to respond to a neurotransmitter called acetylcholine; BFCNs are important for the processes of learning, memory and attention. GDF2 is also important for the maturation of BFCN. Another role of GDF2 has been recently suggested. GDF2 is a potent inducer of hepcidin (a cationic peptide that has antimicrobial properties) in liver cells (hepatocytes) and can regulate iron metabolism. GDF2 is one of the most potent BMPs to induce orthotopic bone formation in vivo. BMP3, a blocker of most BMPs seems not to affect GDF2. GDF2 induces the differentiation of mesenchymal stem cells (MSCs) to an osteoblast lineage. The Smad signaling pathway of GDF2 target HEY1 inducing the differentiation by up regulating it. Augmented expression of HEY1 increase the mineralization of the cells.

GDF3 is a bi-functional protein that has some intrinsic activity and also modulates other TGF-β superfamily members. It may also inhibit other TGF-β superfamily members (i.e. BMPs), thus regulating the balance between different modes of TGF-beta signaling. It has been shown to negatively and positively control differentiation of embryonic stem cells in mice and humans. This molecule plays a role in mesoderm and definitive endoderm formation during the pre-gastrulation stages of development.

GDF6 induces genes related to the development of the epidermis and can bind directly to noggin, a gene that controls neural development, to block its effect. GDF6 interacts with bone morphogenetic proteins (BMPs) to form heterodimers that may work to regulate neural induction and patterning in developing embryos. By developing a GDF6 “knockout” model, scientists repressed expression of GDF6 in developing mice embryos. Through this experiment, the scientists were able to directly link GDF6 with several skull and vertebral joint disorders, such as scoliosis and chondrodysplasia, Grebe type.

GDF9 acts through two receptors on the cells surrounding the oocyte, and it binds to bone morphogenic protein receptor 2 (BMPRII) and downstream to utilize the TGF-β receptor type 1 (ALK5). Ligand receptor activation allows the downstream phosphorylation and activation of SMAD proteins. SMAD proteins are transcription factors found in vertebrates, insects and nematodes, and are the intercellular substrates of all TGF-βmolecules. GDF9 specifically activates SMAD2 and SMAD3 which form a complex with SMAD4, a common partner of all SMAD proteins, that is then able to translocate to the nucleus to regulate gene expression.

In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis. This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in the olfactory epithelium, and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina. Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development. The members of this TGF-β superfamily are involved in the regulation of cell growth and differentiation not only in embryonic tissues, but adult tissues as well.

Role in disease

Mutations in GDF2 have been identified in patients with a vascular disorder phenotypically overlapping with hereditary hemorrhagic telangiectasia.

GDF6 is recurrently amplified and specifically expressed in 80% of the melanomas. Patients with less GDF6 have a lower risk of metastasis and a higher chance of survival. Since GDF6 expression is very low or undetectable in most healthy adult tissues its inhibition could be used to treat this lethal disease.

Polycystic Ovarian Syndrome (PCOS) accounts for approximately 90% of anovulation infertility, affecting 5-10% of woman of reproductive age. In women with PCOS, GDF9 mRNA is decreased in all stages of follicular development compared to women without PCOS. In particular, levels of GDF9 increase as the follicle develops from primordial stages to more mature stages. Women with PCOS have considerably lower expression of GDF9 in primordial, primary and secondary stages of folliculogenesis. GDF9 expression is not only reduced in women with PCOS but also delayed. Despite these facts the exact link of GDF9 with PCOS is not well established.

GDF11 has been identified as a blood circulating factor that has the ability to reverse age-related cardiac hypertrophy in mice. GDF11 gene expression and protein abundance decreases with age, and it shows differential abundance between young and old mice in parabiosis procedures, causing youthful regeneration of cardiomyocytes, a reduction in the brain natriuretic peptide (BNP) and in the atrial natriuretic peptide (ANP). In humans, older males who have been chronically active over their lives show higher concentrations of GDF11 than inactive older men, and the concentration of circulating GDF11 correlates with leg power output when cycling. These results have led to claims that GDF11 may be an anti-aging rejuvenation factor.

GDF15 appears to suppress hepcidin expression during ineffective erythropoiesis, but does not suppress hepcidin in iron deficiency, anemia of chronic disease, or chronic myeloproliferative diseases.

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