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Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.^[1]

Types

Several members of this subfamily have been described, and named GDF1 through GDF15.

GDF1 is expressed chiefly in the nervous system and functions in left-right patterning and mesoderm induction during embryonic development.^[2]
GDF2 (also known as BMP9) induces and maintains the response embryonic basal forebrain cholinergic neurons (BFCN) have to a neurotransmitter called acetylcholine, and regulates iron metabolism by increasing levels of a protein called hepcidin.^[3]^[4]
GDF3 is also known as "Vg-related gene 2" (Vgr-2). Expression of GDF3 occurs in ossifying bone during embryonic development and in the thymus, spleen, bone marrow brain, and adipose tissue of adults. It has a dual nature of function; it both inhibits and induces early stages of development in embryos.^[5]^[6]^[7]
GDF5 is expressed in the developing central nervous system, with roles in the development of joints and the skeleton, and increasing the survival of neurones that respond to a neurotransmitter called dopamine.^[8]^[9]^[10]
GDF6 interacts with bone morphogenetic proteins to regulate ectoderm patterning, and controls eye development.^[11]^[12]^[13]
GDF8 is now officially known as myostatin and controls the growth of muscle tissue.^[14]
GDF9, like GDF3, lacks one cysteine relative to other members of the TGF-β superfamily. Its gene expression is limited to the ovaries, and it has a role in ovulation.^[15]^[16]
GDF10 is closely related to BMP3 and has a roles in head formation and, it is presumed, in skeletal morphogenesis.^[17]^[18] It is also known as BMP-3b.
GDF11 controls anterior-posterior patterning by regulating the expression of Hox genes,^[19] and regulates the number of olfactory receptor neurons occurring in the olfactory epithelium,^[20] and numbers of retinal ganglionic cells developing in the retina.^[21]
GDF15 (also known as TGF-PL, MIC-1, PDF, PLAB, and PTGFB) has a role in regulating inflammatory and apoptotic pathways during tissue injury and certain disease processes.^[22]^[23]^[24]

References

^ Herpin A, Lelong C, Favrel P (2004). "Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans". Dev Comp Immunol. 28 (5): 461–85. doi:10.1016/j.dci.2003.09.007. PMID 15062644.
^ Rankin C, Bunton T, Lawler A, Lee S (2000). "Regulation of left-right patterning in mice by growth/differentiation factor-1". Nat Genet. 24 (3): 262–5. doi:10.1038/73472. PMID 10700179. S2CID 6787053.
^ Lopez-Coviella I, Follettie M, Mellott T, Kovacheva V, Slack B, Diesl V, Berse B, Thies R, Blusztajn J (2005). "Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons". Proc Natl Acad Sci USA. 102 (19): 6984–9. Bibcode:2005PNAS..102.6984L. doi:10.1073/pnas.0502097102. PMC 1088172. PMID 15870197.
^ Truksa J, Peng H, Lee P, Beutler E (2006). "Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6". Proc Natl Acad Sci USA. 103 (27): 10289–93. Bibcode:2006PNAS..10310289T. doi:10.1073/pnas.0603124103. PMC 1502450. PMID 16801541.
^ Levine A, Brivanlou A (2006). "GDF3 at the crossroads of TGF-beta signaling". Cell Cycle. 5 (10): 1069–73. doi:10.4161/cc.5.10.2771. PMID 16721050.
^ Levine A, Brivanlou A (2006). "GDF3, a BMP inhibitor, regulates cell fate in stem cells and early embryos". Development. 133 (2): 209–16. doi:10.1242/dev.02192. PMID 16339188.
^ Chen C, Ware S, Sato A, Houston-Hawkins D, Habas R, Matzuk M, Shen M, Brown C (2006). "The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo". Development. 133 (2): 319–29. doi:10.1242/dev.02210. PMID 16368929.
^ O'Keeffe G, Dockery P, Sullivan A (2004). "Effects of growth/differentiation factor 5 on the survival and morphology of embryonic rat midbrain dopaminergic neurones in vitro". J Neurocytol. 33 (5): 479–88. doi:10.1007/s11068-004-0511-y. PMID 15906156. S2CID 25940876.
^ Buxton P, Edwards C, Archer C, Francis-West P (2001). "Growth/differentiation factor-5 (GDF-5) and skeletal development". J Bone Joint Surg Am. 83-A Suppl 1 (Pt 1): S23–30. PMID 11263662.
^ Francis-West P, Parish J, Lee K, Archer C (1999). "BMP/GDF-signalling interactions during synovial joint development". Cell Tissue Res. 296 (1): 111–9. doi:10.1007/s004410051272. PMID 10199971. S2CID 21942870.
^ Chang C, Hemmati-Brivanlou A (1999). "Xenopus GDF6, a new antagonist of noggin and a partner of BMPs". Development. 126 (15): 3347–57. doi:10.1242/dev.126.15.3347. PMID 10393114.
^ Asai-Coakwell M, French C, Berry K, Ye M, Koss R, Somerville M, Mueller R, van Heyningen V, Waskiewicz A, Lehmann O (2007). "GDF6, a novel locus for a spectrum of ocular developmental anomalies". American Journal of Human Genetics. 80 (2): 306–15. doi:10.1086/511280. PMC 1785352. PMID 17236135.
^ Hanel M, Hensey C (2006). "Eye and neural defects associated with loss of GDF6". BMC Dev Biol. 6: 43. doi:10.1186/1471-213X-6-43. PMC 1609107. PMID 17010201.
^ McPherron AC, Lawler AM, Lee SJ (May 1997). "Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member". Nature. 387 (6628): 83–90. doi:10.1038/387083a0. PMID 9139826. S2CID 4271945.
^ Juengel J, Bodensteiner K, Heath D, Hudson N, Moeller C, Smith P, Galloway S, Davis G, Sawyer H, McNatty K (2004). "Physiology of GDF9 and BMP15 signalling molecules". Anim Reprod Sci. 82–83: 447–60. doi:10.1016/j.anireprosci.2004.04.021. PMID 15271472.
^ Hreinsson J, Scott J, Rasmussen C, Swahn M, Hsueh A, Hovatta O (2002). "Growth differentiation factor-9 promotes the growth, development, and survival of human ovarian follicles in organ culture". J Clin Endocrinol Metab. 87 (1): 316–21. doi:10.1210/jcem.87.1.8185. PMID 11788667.
^ Hino J, Kangawa K, Matsuo H, Nohno T, Nishimatsu S (2004). "Bone morphogenetic protein-3 family members and their biological functions". Front Biosci. 9 (1–3): 1520–9. doi:10.2741/1355. PMID 14977563.
^ Cunningham N, Jenkins N, Gilbert D, Copeland N, Reddi A, Lee S (1995). "Growth/differentiation factor-10: a new member of the transforming growth factor-beta superfamily related to bone morphogenetic protein-3". Growth Factors. 12 (2): 99–109. doi:10.3109/08977199509028956. PMID 8679252.
^ Andersson O, Reissmann E, Ibáñez C (2006). "Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis". EMBO Reports. 7 (8): 831–7. doi:10.1038/sj.embor.7400752. PMC 1525155. PMID 16845371.
^ Wu H, Ivkovic S, Murray R, Jaramillo S, Lyons K, Johnson J, Calof A (2003). "Autoregulation of neurogenesis by GDF11" (PDF). Neuron. 37 (2): 197–207. doi:10.1016/S0896-6273(02)01172-8. PMID 12546816. S2CID 15399794.
^ Kim J, Wu H, Lander A, Lyons K, Matzuk M, Calof A (2005). "GDF11 controls the timing of progenitor cell competence in developing retina". Science. 308 (5730): 1927–30. Bibcode:2005Sci...308.1927K. doi:10.1126/science.1110175. PMID 15976303. S2CID 42002862.
^ Zimmers T, Jin X, Hsiao E, McGrath S, Esquela A, Koniaris L (2005). "Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury". Shock. 23 (6): 543–8. PMID 15897808.
^ Hsiao E, Koniaris L, Zimmers-Koniaris T, Sebald S, Huynh T, Lee S (2000). "Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury". Mol Cell Biol. 20 (10): 3742–51. doi:10.1128/MCB.20.10.3742-3751.2000. PMC 85678. PMID 10779363.
^ Ago T, Sadoshima J (2006). "GDF15, a cardioprotective TGF-beta superfamily protein". Circ Res. 98 (3): 294–7. doi:10.1161/01.RES.0000207919.83894.9d. PMID 16484622.

[herpin-1] Herpin A, Lelong C, Favrel P (2004). "Transforming growth factor-beta-related proteins: an ancestral and widespread superfamily of cytokines in metazoans". Dev Comp Immunol. 28 (5): 461–85. doi:10.1016/j.dci.2003.09.007. PMID 15062644.

[2] Rankin C, Bunton T, Lawler A, Lee S (2000). "Regulation of left-right patterning in mice by growth/differentiation factor-1". Nat Genet. 24 (3): 262–5. doi:10.1038/73472. PMID 10700179. S2CID 6787053.

[lopez-3] Lopez-Coviella I, Follettie M, Mellott T, Kovacheva V, Slack B, Diesl V, Berse B, Thies R, Blusztajn J (2005). "Bone morphogenetic protein 9 induces the transcriptome of basal forebrain cholinergic neurons". Proc Natl Acad Sci USA. 102 (19): 6984–9. Bibcode:2005PNAS..102.6984L. doi:10.1073/pnas.0502097102. PMC 1088172. PMID 15870197.

[4] Truksa J, Peng H, Lee P, Beutler E (2006). "Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6". Proc Natl Acad Sci USA. 103 (27): 10289–93. Bibcode:2006PNAS..10310289T. doi:10.1073/pnas.0603124103. PMC 1502450. PMID 16801541.

[5] Levine A, Brivanlou A (2006). "GDF3 at the crossroads of TGF-beta signaling". Cell Cycle. 5 (10): 1069–73. doi:10.4161/cc.5.10.2771. PMID 16721050.

[6] Levine A, Brivanlou A (2006). "GDF3, a BMP inhibitor, regulates cell fate in stem cells and early embryos". Development. 133 (2): 209–16. doi:10.1242/dev.02192. PMID 16339188.

[7] Chen C, Ware S, Sato A, Houston-Hawkins D, Habas R, Matzuk M, Shen M, Brown C (2006). "The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo". Development. 133 (2): 319–29. doi:10.1242/dev.02210. PMID 16368929.

[8] O'Keeffe G, Dockery P, Sullivan A (2004). "Effects of growth/differentiation factor 5 on the survival and morphology of embryonic rat midbrain dopaminergic neurones in vitro". J Neurocytol. 33 (5): 479–88. doi:10.1007/s11068-004-0511-y. PMID 15906156. S2CID 25940876.

[9] Buxton P, Edwards C, Archer C, Francis-West P (2001). "Growth/differentiation factor-5 (GDF-5) and skeletal development". J Bone Joint Surg Am. 83-A Suppl 1 (Pt 1): S23–30. PMID 11263662.

[10] Francis-West P, Parish J, Lee K, Archer C (1999). "BMP/GDF-signalling interactions during synovial joint development". Cell Tissue Res. 296 (1): 111–9. doi:10.1007/s004410051272. PMID 10199971. S2CID 21942870.

[11] Chang C, Hemmati-Brivanlou A (1999). "Xenopus GDF6, a new antagonist of noggin and a partner of BMPs". Development. 126 (15): 3347–57. doi:10.1242/dev.126.15.3347. PMID 10393114.

[12] Asai-Coakwell M, French C, Berry K, Ye M, Koss R, Somerville M, Mueller R, van Heyningen V, Waskiewicz A, Lehmann O (2007). "GDF6, a novel locus for a spectrum of ocular developmental anomalies". American Journal of Human Genetics. 80 (2): 306–15. doi:10.1086/511280. PMC 1785352. PMID 17236135.

[13] Hanel M, Hensey C (2006). "Eye and neural defects associated with loss of GDF6". BMC Dev Biol. 6: 43. doi:10.1186/1471-213X-6-43. PMC 1609107. PMID 17010201.

[14] McPherron AC, Lawler AM, Lee SJ (May 1997). "Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member". Nature. 387 (6628): 83–90. doi:10.1038/387083a0. PMID 9139826. S2CID 4271945.

[15] Juengel J, Bodensteiner K, Heath D, Hudson N, Moeller C, Smith P, Galloway S, Davis G, Sawyer H, McNatty K (2004). "Physiology of GDF9 and BMP15 signalling molecules". Anim Reprod Sci. 82–83: 447–60. doi:10.1016/j.anireprosci.2004.04.021. PMID 15271472.

[16] Hreinsson J, Scott J, Rasmussen C, Swahn M, Hsueh A, Hovatta O (2002). "Growth differentiation factor-9 promotes the growth, development, and survival of human ovarian follicles in organ culture". J Clin Endocrinol Metab. 87 (1): 316–21. doi:10.1210/jcem.87.1.8185. PMID 11788667.

[17] Hino J, Kangawa K, Matsuo H, Nohno T, Nishimatsu S (2004). "Bone morphogenetic protein-3 family members and their biological functions". Front Biosci. 9 (1–3): 1520–9. doi:10.2741/1355. PMID 14977563.

[cunningham-18] Cunningham N, Jenkins N, Gilbert D, Copeland N, Reddi A, Lee S (1995). "Growth/differentiation factor-10: a new member of the transforming growth factor-beta superfamily related to bone morphogenetic protein-3". Growth Factors. 12 (2): 99–109. doi:10.3109/08977199509028956. PMID 8679252.

[andersson-19] Andersson O, Reissmann E, Ibáñez C (2006). "Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis". EMBO Reports. 7 (8): 831–7. doi:10.1038/sj.embor.7400752. PMC 1525155. PMID 16845371.

[20] Wu H, Ivkovic S, Murray R, Jaramillo S, Lyons K, Johnson J, Calof A (2003). "Autoregulation of neurogenesis by GDF11" (PDF). Neuron. 37 (2): 197–207. doi:10.1016/S0896-6273(02)01172-8. PMID 12546816. S2CID 15399794.

[21] Kim J, Wu H, Lander A, Lyons K, Matzuk M, Calof A (2005). "GDF11 controls the timing of progenitor cell competence in developing retina". Science. 308 (5730): 1927–30. Bibcode:2005Sci...308.1927K. doi:10.1126/science.1110175. PMID 15976303. S2CID 42002862.

[zimmers-22] Zimmers T, Jin X, Hsiao E, McGrath S, Esquela A, Koniaris L (2005). "Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury". Shock. 23 (6): 543–8. PMID 15897808.

[hsiao-23] Hsiao E, Koniaris L, Zimmers-Koniaris T, Sebald S, Huynh T, Lee S (2000). "Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury". Mol Cell Biol. 20 (10): 3742–51. doi:10.1128/MCB.20.10.3742-3751.2000. PMC 85678. PMID 10779363.

[24] Ago T, Sadoshima J (2006). "GDF15, a cardioprotective TGF-beta superfamily protein". Circ Res. 98 (3): 294–7. doi:10.1161/01.RES.0000207919.83894.9d. PMID 16484622.

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