GDF11

Growth differentiation factor 11
Identifiers
Symbols GDF11 ; BMP-11; BMP11
External IDs OMIM: 603936 MGI: 1338027 HomoloGene: 21183 GeneCards: GDF11 Gene
Orthologs
Species Human Mouse
Entrez 10220 14561
Ensembl ENSG00000135414 ENSMUSG00000025352
UniProt O95390 Q9Z1W4
RefSeq (mRNA) NM_005811 NM_010272
RefSeq (protein) NP_005802 NP_034402
Location (UCSC) Chr 12:
55.74 – 55.76 Mb		 Chr 10:
128.88 – 128.89 Mb
PubMed search

Growth differentiation factor 11 (GDF11) also known as bone morphogenetic protein 11 (BMP-11) is a protein that in humans is encoded by the GDF11 gene.[1]

It acts as a cytokine.

The BMP group of proteins is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues.[2] GDF11 is a myostatin-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.[3] 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.[3]

In 2014, GDF11 was described as an anti-aging factor in two publications based on the results of a parabiosis experiments with mice [4][5] that were chosen as Science's scientific breakthrough of the year.[6] Later studies questioned these findings.[7][8][9][10] Researchers disagree on the selectivity of the tests used to measure GDF11 and on the activity of GDF11 from various commercially-available sources.[11] The full relationship of GDF11 to aging—and any possible differences in the action of GDF11 in mice, rats, and humans—is unclear and continues to be researched.

Effects on cell growth and differentiation

GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes.[12] It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.[13]

During mouse development, GDF11 expression begins in the tail bud and caudal neural plate region. GDF knock-out mice display skeletal defects as a result of patterning problems with anterior-posterior positioning.[14]

In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis.[5]

This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in the olfactory epithelium,[15] and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina.[16] 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.[17]

GDF11 can bind type I TGF-beta superfamily receptors ACVR1B (ALK4), TGFBR1 (ALK5) and ACVR1C (ALK7), but predominantly uses ALK4 and ALK5 for signal transduction.[12]

GDF11 is closely related to myostatin, a negative regulator of muscle growth.[18][19] Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation. GDF11 is also a negative regulator of neurogenesis,[1][15] the production of islet progenitor cells,[20] the regulation of kidney organogenesis,[21] pancreatic development,[22] the rostro-caudal patterning in the development of spinal cords,[13] and is a negative regulator of chondrogenesis.[23]

Due to the similarities between myostatin and GDF11, the actions of GDF11 are likely regulated by WFIKKN2, a large extracellular multidomain protein consisting of follistatin, immunoglobulin, protease inhibitor, and NTR domains.[24] WFIKKN2 has a high affinity for GDF11, and previously has been found to inhibit the biological activities of myostatin.[25]

Effect on cardiac and skeletal muscle aging

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). GDF11 also causes an increase in expression of SERCA-2, an enzyme necessary for relaxation during diastolic functions.[26] GDF11 activates the TGF-β pathway in cardiomyocytes derived from pluripotent hematopoietic stem cells and suppresses the phosphorylation of Forkhead (FOX proteins) transcription factors. These effects suggest an "anti-hypertrophic effect", aiding in the reversal process of age-related hypertrophy, on the cardiomyocytes.[26] In 2014, peripheral supplementation of GDF11 protein (in mice) was shown to ameliorate the age-related dysfunction of skeletal muscle by rescuing the function of aged muscle stem cells, claiming that GDF11 may be an anti-aging rejuvenation factor.[4]

These previous findings have been disputed since another publication has demonstrated the contrary, concluding that GDF11 increases with age and has deleterious effects on skeletal muscle regeneration,[7] being a pro-aging factor, with very high levels in some aged individuals. However, in October 2015, these contrary results have been shown to be the result of a flawed assay that was detecting immunoglobulin and not GDF11. The newer Harvard study claimed GDF11 does in fact reverse age-related cardiac hypertrophy.[11] However this newer study both ignored the GDF11-specific assay that was developed, establishing that GDF11 in mice is undetectable, and that the factor measured was in fact myosatin.[7] Also, the newer study combined the measure of GDF11 and GDF8 (myostatin), using a non-specific antibody, further confusing matters. More research is needed in this area.

References

  1. 1 2 Ge G, Hopkins DR, Ho WB, Greenspan DS (Jul 2005). "GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells". Molecular and Cellular Biology 25 (14): 5846–58. doi:10.1128/MCB.25.14.5846-5858.2005. PMC 1168807. PMID 15988002.
  2. ↑ "Gene GDF11". Genecards. Retrieved 25 May 2013.
  3. 1 2 "Recombinant-Human GDF11".
  4. 1 2 Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ (May 2014). "Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle". Science 344 (6184): 649–52. doi:10.1126/science.1251152. PMID 24797481.
  5. 1 2 Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL (May 2014). "Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors". Science 344 (6184): 630–4. doi:10.1126/science.1251141. PMID 24797482.
  6. ↑ http://www.thecherrycreeknews.com/young-blood-reverses-aging-breakthrough-2014-gdf11/
  7. 1 2 3 Egerman MA, Cadena SM, Gilbert JA, Meyer A, Nelson HN, Swalley SE, Mallozzi C, Jacobi C, Jennings LL, Clay I, Laurent G, Ma S, Brachat S, Lach-Trifilieff E, Shavlakadze T, Trendelenburg AU, Brack AS, Glass DJ (Jul 2015). "GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration". Cell Metabolism 22 (1): 164–74. doi:10.1016/j.cmet.2015.05.010. PMID 26001423.
  8. ↑ Age-reversal effects of 'young blood' molecule GDF-11 called into question, retrieved 20 May 2015
  9. ↑ 'Young blood' anti-ageing mechanism called into question, retrieved 20 May 2015
  10. ↑ Smith SC, Zhang X, Zhang X, Gross P, Starosta T, Mohsin S, Franti M, Gupta P, Hayes D, Myzithras M, Kahn J, Tanner J, Weldon SM, Khalil A, Guo X, Sabri A, Chen X, MacDonnell S, Houser SR (Nov 2015). "GDF11 Does Not Rescue Aging-Related Pathological Hypertrophy". Circulation Research 117 (11): 926–32. doi:10.1161/CIRCRESAHA.115.307527. PMID 26383970.
  11. 1 2 Kaiser J (Oct 2015). "Antiaging protein is the real deal, Harvard team claims". Science. doi:10.1126/science.aad4748.
  12. 1 2 Andersson O, Reissmann E, Ibáñez CF (Aug 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.
  13. 1 2 Liu JP (Aug 2006). "The function of growth/differentiation factor 11 (Gdf11) in rostrocaudal patterning of the developing spinal cord". Development 133 (15): 2865–74. doi:10.1242/dev.02478. PMID 16790475.
  14. ↑ McPherron AC, Lawler AM, Lee SJ (Jul 1999). "Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11". Nature Genetics 22 (3): 260–4. doi:10.1038/10320. PMID 10391213.
  15. 1 2 Wu HH, Ivkovic S, Murray RC, Jaramillo S, Lyons KM, Johnson JE, Calof AL (Jan 2003). "Autoregulation of neurogenesis by GDF11". Neuron 37 (2): 197–207. doi:10.1016/S0896-6273(02)01172-8. PMID 12546816.
  16. ↑ Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL (Jun 2005). "GDF11 controls the timing of progenitor cell competence in developing retina". Science 308 (5730): 1927–30. doi:10.1126/science.1110175. PMID 15976303.
  17. ↑ "GDF11". Genecards.
  18. ↑ McPherron AC, Lee SJ (Nov 1997). "Double muscling in cattle due to mutations in the myostatin gene". Proceedings of the National Academy of Sciences of the United States of America 94 (23): 12457–61. doi:10.1073/pnas.94.23.12457. PMC 24998. PMID 9356471.
  19. ↑ Lee SJ, McPherron AC (Oct 1999). "Myostatin and the control of skeletal muscle mass". Current Opinion in Genetics & Development 9 (5): 604–7. doi:10.1016/S0959-437X(99)00004-0. PMID 10508689.
  20. ↑ Harmon EB, Apelqvist AA, Smart NG, Gu X, Osborne DH, Kim SK (Dec 2004). "GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development". Development 131 (24): 6163–74. doi:10.1242/dev.01535. PMID 15548585.
  21. ↑ Esquela AF, Lee SJ (May 2003). "Regulation of metanephric kidney development by growth/differentiation factor 11". Developmental Biology 257 (2): 356–70. doi:10.1016/s0012-1606(03)00100-3. PMID 12729564.
  22. ↑ Dichmann DS, Yassin H, Serup P (Nov 2006). "Analysis of pancreatic endocrine development in GDF11-deficient mice". Developmental Dynamics 235 (11): 3016–25. doi:10.1002/dvdy.20953. PMID 16964608.
  23. ↑ Gamer LW, Cox KA, Small C, Rosen V (Jan 2001). "Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb". Developmental Biology 229 (2): 407–20. doi:10.1006/dbio.2000.9981. PMID 11203700.
  24. ↑ "Both WFIKKN1 and WFIKKN2 Have High Affinity for Growth and Differentiation Factors 8 and 11". NCBI. Retrieved 25 May 2013.
  25. ↑ "WJIKKN2". Geneards. Retrieved 25 May 2013.
  26. 1 2 Loffredo FS, Steinhauser ML, Jay SM, Gannon J, Pancoast JR, Yalamanchi P, Sinha M, Dall'Osso C, Khong D, Shadrach JL, Miller CM, Singer BS, Stewart A, Psychogios N, Gerszten RE, Hartigan AJ, Kim MJ, Serwold T, Wagers AJ, Lee RT (May 2013). "Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy". Cell 153 (4): 828–39. doi:10.1016/j.cell.2013.04.015. PMID 23663781.

Further reading

External links

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