GDF11

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Growth differentiation factor 11
Identifiers
Symbols GDF11 ; BMP-11; BMP11
External IDs OMIM603936 MGI1338027 HomoloGene21183 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:
56.14 – 56.15 Mb
Chr 10:
128.88 – 128.89 Mb
PubMed search [1] [2]

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] This 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]

Effects on cell growth and differentiation[edit]

GDF11 belongs to the transforming growth factor beta superfamily that controls anterior-posterior patterning by regulating the expression of Hox genes.[4] It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord.[5]

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.[6] Peripheral supplementation of GDF11 protein (in mice) ameliorates the age-related dysfunction of skeletal muscle by rescuing the function of aged muscle stem cells.[7]

In the mouse adult central nervous system, GDF11 alone can improve the cerebral vasculature and enhance neurogenesis..[8]

This cytokine also inhibits the proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons occurring in the olfactory epithelium,[9] and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina.[10] 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.[11]

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.[4]

GDF11 is closely related to myostatin, a negative regulator of muscle growth.[12][13] Both myostatin and GDF11 are involved in the regulation of cardiomyocyte proliferation. GDF11 is also a negative regulator of neurogenesis,[14][15] the production of islet progenitor cells,[16] the regulation of kidney organogenesis,[17] pancreatic development,[18] the rostro-caudal patterning in the development of spinal cords,[19] and is a negative regulator of chondrogenesis.[20]

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.[21] WFIKKN2 has a high affinity for GDF11, and previously has been found to inhibit the biological activities of myostatin.[22]

Effect on cardiac aging[edit]

GDF11 has been identified as a blood circulating factor that has the ability to reverse cardiac hypertrophy in mice as a result of hypertrophy related to aging. 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.[23] 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.[23]

References[edit]

  1. ^ Ge G, Hopkins DR, Ho WB, Greenspan DS (July 2005). "GDF11 forms a bone morphogenetic protein 1-activated latent complex that can modulate nerve growth factor-induced differentiation of PC12 cells". Mol. Cell. Biol. 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. ^ a b "Recombinant-Human GDF11". 
  4. ^ a b 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 Rep 7 (8): 831–7. doi:10.1038/sj.embor.7400752. PMC 1525155. PMID 16845371. 
  5. ^ Liu J (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. 
  6. ^ McPherron, AC; Lawler, AM; Lee, SJ (July 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. 
  7. ^ Sinha, M; Jang, YC; Oh, J; Khong, D; ... 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. 
  8. ^ Katsimpardi, L; Litterman, NK; Schein PA; Miller CM; Loffredo FS; Wojtkiewicz GR (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. 
  9. ^ Wu H, Ivkovic S, Murray R, Jaramillo S, Lyons K, Johnson J, Calof A (2003). "Autoregulation of neurogenesis by GDF11". Neuron 37 (2): 197–207. doi:10.1016/S0896-6273(02)01172-8. PMID 12546816. 
  10. ^ 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. doi:10.1126/science.1110175. PMID 15976303. 
  11. ^ "GDF11". Genecards. 
  12. ^ McPherron, Alexandra; Se-Jin Lee (November 1997). "Double muscling in cattle due to mutations in the myostatin gene". PNAS 94 (23): 12457–12461. doi:10.1073/pnas.94.23.12457. PMC 24998. PMID 9356471. Retrieved 25 May 2013. 
  13. ^ Lee, SJ; McPherron, AC (October 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. 
  14. ^ Wu, HH; Ivkovic, S; Murray, RC; Jaramillo, S; Lyons, KM; Johnson, JE; Calof, AL (Jan 23, 2003). "Autoregulation of neurogenesis by GDF11.". Neuron 37 (2): 197–207. doi:10.1016/S0896-6273(02)01172-8. PMID 12546816. 
  15. ^ Ge, G; Hopkins, DR; Ho, WB; Greenspan, DS (July 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. 
  16. ^ Harmon, EB; Apelqvist, AA; Smart, NG; Gu, X; Osborne, DH; Kim, SK (December 2004). "GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development.". Development (Cambridge, England) 131 (24): 6163–74. doi:10.1242/dev.01535. PMID 15548585. 
  17. ^ Esquela, AF; Lee, SJ (May 15, 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. 
  18. ^ Dichmann, DS; Yassin, H; Serup, P (November 2006). "Analysis of pancreatic endocrine development in GDF11-deficient mice.". Developmental dynamics : an official publication of the American Association of Anatomists 235 (11): 3016–25. doi:10.1002/dvdy.20953. PMID 16964608. 
  19. ^ Liu, JP (August 2006). "The function of growth/differentiation factor 11 (Gdf11) in rostrocaudal patterning of the developing spinal cord.". Development (Cambridge, England) 133 (15): 2865–74. doi:10.1242/dev.02478. PMID 16790475. 
  20. ^ Gamer, LW; Cox, KA; Small, C; Rosen, V (Jan 15, 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. 
  21. ^ "Both WFIKKN1 and WFIKKN2 Have High Affinity for Growth and Differentiation Factors 8 and 11". NCBI. Retrieved 25 May 2013. 
  22. ^ "WJIKKN2". Geneards. Retrieved 25 May 2013. 
  23. ^ a b Loffredo, Francesco; et al (9 May 2013). "Growth Differentiation Factor Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy". Cell 153: 828–839. doi:10.1016/j.cell.2013.04.015. 


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