growth/differentiation factor 11; GDF-11; bone morphogenetic protein 11; BMP-11 (GDF11, BMP11)
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Function
- secreted signal that acts globally to specify positional identity along the anterior/posterior axis during development
- role in patterning both mesodermal & neural tissues & in establishing the skeletal pattern
- inhibitor of nerve tissue growth[4][5]
- arrest of progenitor cell-cycle in the G1 phase
- interacts with ALK4 & ALK5 to activate SMAD3-dependent genes[6]
- may upregulate expression of Hoxc10[6]
- inhibits proliferation of olfactory receptor neuron progenitors to regulate the number of olfactory receptor neurons in the olfactory epithelium by inducing p27(Kip1) & reversible cell cycle arrest in progenitors[7]
- controls the numbers of retinal ganglion cells, amacrine cells & photoreceptor cells during development of the retina[8]
- in the retina, does not affect proliferation of <A1005>progenitor cells</A1005>
- controls duration of expression of Math5, a gene that confers competence for retinal ganglion cell genesis
- thus controls temporal windows for progenitor cell competence[8]
- increases expression of SERCA2 in myocardium, an enzyme necessary for relaxation during diastole
- negatively regulates
- cardiomyocyte proliferation
- neurogenesis[7]
- islet cell proliferation
- promotes beta-cell differentiation*
- renal progenitor cell proliferation
- chondrocyte proliferation
- may be regulated by WFIKKN2
* perhaps in general, inhibits proliferation, promotes differentiation
Structure
- homodimer; disulfide-linked (putative)
- belongs to the TGF-beta family
- homologous to myostatin & may play similar cellular role[4]
- 90% identical in their amino acid sequence[5]
- 89% homlogous to GDF8[12]
Compartment
secreted (probable)
Expression
- GDF11 gene expression & protein abundance decreases with age[2][4]
- GDF11 plasma levels may increase with age[11]
- GDF11 plasma levels decline with age in mice, rats, horses & sheep[12]
Comparative biology
- GDF11 reverses LV diastolic dysfunction in mice[1]
- blood of young mice contains substances that reverse aging processes in heart muscle, skeletal muscle, & brain
- one of these substances is GDF11[3]
- GDF11 inhibits muscle regeneration in mice[11]
- effect may be dose-sensitive (therapeutic window)[11]
- one dose may enhance muscle regeneration, but a 3-fold dose increase may inhibit muscle regeneration[11]
- effect may be dose-sensitive (therapeutic window)[11]
- plasma levels of GDF11 do not decline with age[11]*
- it is noted that there may be several forms of GDF11 in mice & that some forms may decline with age while others may increase[11]
- plasma GDF11 & GDF11 mRNA in muscle increase with age in rats[11]
- circulating levels of GDF11 decline with age in mice, rats, horses & sheep[12]
- in patients with stable ischemic heart disease, higher GDF11/GDF8 (myostatin) levels are associated with lower risk of cardiovascular events & death[13]*
* ref[12] claims increase in GDF11 levels with age observed in ref[11] are a result of cross-reactivity of the anti-GDF11 antibody used in ref[11] with immunoglobulin
More general terms
References
- ↑ 1.0 1.1 UniProt http://www.uniprot.org/uniprot/O95390.html
- ↑ 2.0 2.1 Loffredo FS et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 2013 May 9; 153:828 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23663781
- ↑ 3.0 3.1 Sinha M et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 2014 May 9; 344:649. PMID: https://www.ncbi.nlm.nih.gov/pubmed/24797481
Katsimpardi L et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 2014 May 9; 344:630. (http://dx.doi.org/10.1126/science.1251141) PMID: https://www.ncbi.nlm.nih.gov/pubmed/24797482
Villeda SA et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014 May 4 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24793238 - ↑ 4.0 4.1 4.2 4.3 Wikipedia: GDF11 http://en.wikipedia.org/wiki/GDF11
- ↑ 5.0 5.1 5.2 Recombinant Human GDF-11 http://www.peprotech.com/en-US/Pages/Product/Recombinant-Proteins/Growth-Factors-Cytokines/Recombinant_Human_GDF-11/120-11
- ↑ 6.0 6.1 6.2 Andersson O, Reissmann E, Ibanez CF. Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis. EMBO Rep. 2006 Aug;7(8):831-7. Epub 2006 Jul 14. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16845371
- ↑ 7.0 7.1 7.2 Wu HH, Ivkovic S, Murray RC et al Autoregulation of neurogenesis by GDF11. Neuron. 2003 Jan 23;37(2):197-207. PMID: https://www.ncbi.nlm.nih.gov/pubmed/12546816
- ↑ 8.0 8.1 8.2 Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL GDF11 controls the timing of progenitor cell competence in developing retina. Science. 2005 Jun 24;308(5730):1927-30. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15976303
- ↑ Harmon EB, Apelqvist AA, Smart NG, Gu X, Osborne DH, Kim SK. GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development. 2004 Dec;131(24):6163-74. Epub 2004 Nov 17. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15548585
- ↑ Kondas K, Szlama G, Trexler M, Patthy L Both WFIKKN1 and WFIKKN2 Have High Affinity for Growth and Differentiation Factors 8 and 11. J Biol Chem. Aug 29, 2008; 283(35): 23677-23684 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/18596030 <Internet> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3259755/#!po=73.8095
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 Kaiser J Doubts cast on 'rejuvenating' protein. Science Daily News. May 19, 2015 http://news.sciencemag.org/biology/2015/05/doubts-cast-rejuvenating-protein
- ↑ 12.0 12.1 12.2 12.3 12.4 Poggioli1 T, Vujic A, Yang P et al Circulating Growth Differentiation Factor 11/8 Levels Decline with Age. Circ Res. Oct 21, 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26489925 <Internet> http://circres.ahajournals.org/content/early/2015/10/21/CIRCRESAHA.115.307521.abstract
- ↑ 13.0 13.1 Olson KA, Beatty AL, Heidecker B et al Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes & overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts. European Heart Journal. Aug 20, 2015 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/26294790 <Internet> http://eurheartj.oxfordjournals.org/content/early/2015/08/20/eurheartj.ehv385