GDF11

Last updated

GDF11
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases GDF11 , BMP-11, BMP11, growth differentiation factor 11, VHO
External IDs OMIM: 603936; MGI: 1338027; HomoloGene: 21183; GeneCards: GDF11; OMA:GDF11 - orthologs
Orthologs
SpeciesHumanMouse
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: 128.72 – 128.73 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] GDF11 is a member of the Transforming growth factor beta family. [6]

Contents

GDF11 acts as a cytokine and its sequence is highly conserved between in humans, mice and rats. [7] The bone morphogenetic protein group is characterized by a polybasic proteolytic processing site, which is cleaved to produce a protein containing seven conserved cysteine residues. [8]

Tissue distribution

GDF11 is expressed in many tissues, including skeletal muscle, pancreas, skin, kidney, nervous system, and retina. [6]

Function

Gene deletion and over-expression studies indicate that GDF11 primarily regulates the embryological development of the skeletal system. It may also help regulate development of the central nervous system, blood vessels, the kidney and other tissues. [9] [10] [11] [12] [13]

GDF11 was initially reported to improve neurodegenerative and neurovascular disease outcomes, increase skeletal muscle volume, and enhances muscle strength [14] . However, several groups then showed that over-expression of GDF11 causes muscle wasting. In retrospect, this is not surprising, since GDF11 is 90% identical to myostatin, a known inhibitor of muscle growth. GDF11 binds the same ActRIIA/B receptors, initiating phosphorylation of the SMAD2/3 transcription factors [15] .

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. [16] It determines Hox gene expression domains and rostrocaudal identity in the caudal spinal cord. [12]

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. [17] This cytokine also inhibits the proliferation of olfactory receptor neural progenitors to regulate the number of neurons in the olfactory epithelium, [18] and controls the competence of progenitor cells to regulate numbers of retinal ganglionic cells developing in the retina. [19] Other studies in mice suggest that GDF11 is involved in mesodermal formation and neurogenesis during embryonic development.

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. [16] It is also closely related to myostatin, a negative regulator of muscle growth, [20] [21] both structurally and phylogenetically. [22]

GDF11 is 90% structurally similar to myostatin. It was originally reported that GDF11 levels decline with age and exerts anti-aging regenerative effects in skeletal muscle in mice [23] . However, it was later shown that the reagents used were non-selective, and the authors were measuring myostatin, not GDF11 [24] . GDF11 does not decline with age, and its downstream signaling mechanisms are similar to that of myostatin.

Human studies

Elevian, a university spin-off company whose founders include Harvard Stem Cell Institute researchers Dr. Amy Wagers, Dr. Lee Rubin, and Dr. Rich Lee, has raised $58 million in two rounds of funding to study GDF11. On June 19, 2022, the New York Times published an article about GDF11 and Elevian titled "Can a 'Magic' Protein Slow the Aging Process?". [25] The article stated that Elevian will conduct clinical trials using GDF11 to repair stroke damage in humans starting in Q1 of 2023. [25]

GDF11 levels in individuals with major depressive disorder are significantly lower compared to healthy controls. Administration of GDF11 in aged mice stimulates neuronal autophagy which improves memory and alleviates senescence and depression-like symptoms in a neurogenesis-independent manner. [26] flammation, which could be the cause higher GDF11 expression in colon cancer patients.. [27]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000135414 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025352 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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): 5846–5858. doi:10.1128/MCB.25.14.5846-5858.2005. PMC   1168807 . PMID   15988002.
  6. 1 2 Simoni-Nieves A, Gerardo-Ramírez M, Pedraza-Vázquez G, Chávez-Rodríguez L, Bucio L, Souza V, et al. (2019). "GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies". Frontiers in Oncology. 9 1039. doi: 10.3389/fonc.2019.01039 . PMC   6803553 . PMID   31681577.
  7. ↑ Jamaiyar A, Wan W, Janota DM, Enrick MK, Chilian WM, Yin L (July 2017). "The versatility and paradox of GDF 11". Pharmacology & Therapeutics. 175: 28–34. doi:10.1016/j.pharmthera.2017.02.032. PMC   6319258 . PMID   28223232.
  8. ↑ "Gene GDF11". Genecards. Retrieved 25 May 2013.
  9. ↑ Egerman MA, Glass DJ (April 2019). "The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis". Critical Reviews in Biochemistry and Molecular Biology. 54 (2): 174–183. doi:10.1080/10409238.2019.1610722. PMID   31144559. S2CID   169039791.
  10. ↑ Esquela AF, Lee SJ (May 2003). "Regulation of metanephric kidney development by growth/differentiation factor 11". Developmental Biology. 257 (2): 356–370. doi: 10.1016/s0012-1606(03)00100-3 . PMID   12729564.
  11. ↑ Dichmann DS, Yassin H, Serup P (November 2006). "Analysis of pancreatic endocrine development in GDF11-deficient mice". Developmental Dynamics. 235 (11): 3016–3025. doi: 10.1002/dvdy.20953 . PMID   16964608. S2CID   30675774.
  12. 1 2 Liu JP (August 2006). "The function of growth/differentiation factor 11 (Gdf11) in rostrocaudal patterning of the developing spinal cord". Development. 133 (15): 2865–2874. doi: 10.1242/dev.02478 . PMID   16790475.
  13. ↑ Gamer LW, Cox KA, Small C, Rosen V (January 2001). "Gdf11 is a negative regulator of chondrogenesis and myogenesis in the developing chick limb". Developmental Biology. 229 (2): 407–420. doi: 10.1006/dbio.2000.9981 . PMID   11203700.
  14. ↑ Egerman MA, Glass DJ (April 2019). "The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis". Critical Reviews in Biochemistry and Molecular Biology. 54 (2): 174–183. doi:10.1080/10409238.2019.1610722. PMID   31144559. S2CID   169039791.
  15. ↑ Egerman MA, Glass DJ (April 2019). "The role of GDF11 in aging and skeletal muscle, cardiac and bone homeostasis". Critical Reviews in Biochemistry and Molecular Biology. 54 (2): 174–183. doi:10.1080/10409238.2019.1610722. PMID   31144559. S2CID   169039791.
  16. 1 2 Andersson O, Reissmann E, Ibáñez CF (August 2006). "Growth differentiation factor 11 signals through the transforming growth factor-beta receptor ALK5 to regionalize the anterior-posterior axis". EMBO Reports. 7 (8): 831–837. doi:10.1038/sj.embor.7400752. PMC   1525155 . PMID   16845371.
  17. ↑ 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): 260–264. doi:10.1038/10320. PMID   10391213. S2CID   1172738.
  18. ↑ Wu HH, Ivkovic S, Murray RC, Jaramillo S, Lyons KM, Johnson JE, et al. (January 2003). "Autoregulation of neurogenesis by GDF11". Neuron. 37 (2): 197–207. doi: 10.1016/S0896-6273(02)01172-8 . PMID   12546816. S2CID   15399794.
  19. ↑ Kim J, Wu HH, Lander AD, Lyons KM, Matzuk MM, Calof AL (June 2005). "GDF11 controls the timing of progenitor cell competence in developing retina". Science. 308 (5730): 1927–1930. Bibcode:2005Sci...308.1927K. doi:10.1126/science.1110175. PMID   15976303. S2CID   42002862.
  20. ↑ McPherron AC, Lee SJ (November 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): 12457–12461. Bibcode:1997PNAS...9412457M. doi: 10.1073/pnas.94.23.12457 . PMC   24998 . PMID   9356471.
  21. ↑ Lee SJ, McPherron AC (October 1999). "Myostatin and the control of skeletal muscle mass". Current Opinion in Genetics & Development. 9 (5): 604–607. doi: 10.1016/S0959-437X(99)00004-0 . PMID   10508689.
  22. ↑ Kerr T, Roalson EH, Rodgers BD (2005). "Phylogenetic analysis of the myostatin gene sub-family and the differential expression of a novel member in zebrafish". Evolution & Development. 7 (5): 390–400. Bibcode:2005EvDev...7..390K. doi:10.1111/j.1525-142X.2005.05044.x. PMID   16174033. S2CID   6538603.
  23. ↑ Lofreddo FS, et al. (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. PMC   3677132 .
  24. ↑ Egerman MA, et al. (July 2015). "GDF11 Increases with Age and Inhibits Skeletal Muscle Regeneration". Cell Metabolism. 2 (1): 164–74. doi:10.1016/j.cmet.2015.05.010. PMC   4497834 .
  25. 1 2 Zimmerman E (2022-07-19). "Can a 'Magic' Protein Slow the Aging Process?". The New York Times. ISSN   0362-4331 . Retrieved 2022-12-05.
  26. ↑ Moigneu C, Abdellaoui S, Ramos-Brossier M, Pfaffenseller B, Wollenhaupt-Aguiar B, de Azevedo Cardoso T, et al. (2023-02-02). "Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy". Nature Aging. 3 (2): 213–228. doi:10.1038/s43587-022-00352-3. ISSN   2662-8465. PMC   10154197 . PMID   37118117.
  27. ↑ Simoni-Nieves A, Gerardo-Ramírez M, Pedraza-Vázquez G, Chávez-Rodríguez L, Bucio L, Souza V, et al. (2019-10-15). "GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies". Frontiers in Oncology. 9 1039. doi: 10.3389/fonc.2019.01039 . PMC   6803553 . PMID   31681577.

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