Cerberus is an inhibitor in the TGF beta signaling pathway secreted during the gastrulation phase of embryogenesis. Cerberus (Cer) is a gene that encodes a cytokine (a secreted signaling protein) important for induction and formation of the heart and head in vertebrates. The Cerberus gene encodes a polypeptide that is 270 amino acids in length and is expressed in the anterior domain of a gastrula in the endoderm layer. Cerberus also plays a large role as an inhibitory molecule, which is important for proper head induction. Cerberus inhibits the proteins bone morphogenetic protein 4 (BMP4), Xnr1, and Xwnt8.
This gene encodes a cytokine member of the cystine knot superfamily, characterized by nine conserved cysteines and a cysteine knot region. The cerberus-related cytokines, together with Dan and DRM / Gremlin, represent a group of bone morphogenetic protein (BMP) antagonists that can bind directly to BMPs and inhibit their activity.
In human embryonic development, Cerberus and the protein coded by GREM3 inhibit NODAL in the Wnt signaling pathway during the formation of the germ layers. Specifically, Cerberus and GREM3 act as antagonists to Nodal in the anterior region of the developing embryo, blocking its expression and halting the progression of the primitive node. Orthologs of the gene that codes Cerberus (CER1) are conserved in other non-rodent mammals, indicating that Cerberus has similar functions in other vertebrates.
A gene knockdown experiment was conducted in Xenopus, where the amount of Cerberus expressed was decreased by inhibiting translation. The proteins that Cerberus inhibits (BMP4, Xnr1, Xwnt8) concentrations were increased also. It was also shown that just the decrease of Cerberus translation alone was not enough to inhibit the formation of head structures. While the increase of just BMP4, Xnr1, Xwnt8 led to defects in the formation of the head. The increase of BMP4, Xnr1, Xwnt8 and the decrease of Cerberus together blocked the formation of the head. This gene knockdown experiment showed the necessity of Cerberus’ inhibitory functions in the formation of head structures. It quite possibly may be that although Cerberus is necessary for the induction of a head, its inhibitory actions may play a more significant role in ensuring the head is developed properly.
Overexpression or overabundance of Cerberus is associated with the development of ectopic heads. These additional head-like structures may contain varying characteristics of a normal head (eye or eyes, brain, notochord) depending on the ratio of overabundant Cerberus to other proteins associated with anterior development that Cerberus inhibits (Wnt, Nodal, and BMP). If only Nodal is blocked, a single head will still form but with abnormalities such as cyclopia. If both Nodal and BMP or Wnt and BMP are sufficiently inhibited, ectopic, abnormal head-like structures will form. Inhibition of all three proteins by Cerberus is required for the development of complete, ectopic heads.
During mammalian heart induction, a mammalian homologue, Cer1, is associated with the coordinated suppression of the TGFbeta superfamily members Nodal and BMP. This induces Brahma-associated factor 60c (Baf60c), one of three Baf60 variants (a, b, and c) that are mutually exclusively assembled into the SWI/SNFchromatin remodelling complex. Blocking Nodal and BMP also induces lineage-specific transcription factors Gata4 and Tbx5, which interact with Baf60c. Collectively, these proteins redirect SWI/SNF to activate the cardiac program of gene expression. Targeted inactivation of another homologue, Cerberus like-2 (Cerl2), in the mouse leads to left ventricular cardiac hyperplasia and systolic dysfunction.
^Lah M, Brodnicki T, Maccarone P, Nash A, Stanley E, Harvey RP (February 1999). "Human cerberus related gene CER1 maps to chromosome 9". Genomics. 55 (3): 364–6. doi:10.1006/geno.1998.5671. PMID10049596.
^Bouwmeester T, Kim S, Sasai Y, Lu B, De Robertis EM (August 1996). "Cerberus is a head-inducing secreted factor expressed in the anterior endoderm of Spemann's organizer". Nature. 382 (6592): 595–601. doi:10.1038/382595a0. PMID8757128.
^Katoh M, Katoh M (May 2006). "CER1 is a common target of WNT and NODAL signaling pathways in human embryonic stem cells". International Journal of Molecular Medicine. 17 (5): 795–9. doi:10.3892/ijmm.17.5.795. PMID16596263.
^Silva AC, Filipe M, Kuerner KM, Steinbeisser H, Belo JA (October 2003). "Endogenous Cerberus activity is required for anterior head specification in Xenopus". Development. 130 (20): 4943–53. doi:10.1242/dev.00705. PMID12952900.
Swinkels ME, Simons A, Smeets DF, Vissers LE, Veltman JA, Pfundt R, de Vries BB, Faas BH, Schrander-Stumpel CT, McCann E, Sweeney E, May P, Draaisma JM, Knoers NV, van Kessel AG, van Ravenswaaij-Arts CM (June 2008). "Clinical and cytogenetic characterization of 13 Dutch patients with deletion 9p syndrome: Delineation of the critical region for a consensus phenotype". American Journal of Medical Genetics. Part A. 146A (11): 1430–8. doi:10.1002/ajmg.a.32310. PMID18452192.
Tang PL, Cheung CL, Sham PC, McClurg P, Lee B, Chan SY, Smith DK, Tanner JA, Su AI, Cheah KS, Kung AW, Song YQ (June 2009). "Genome-wide haplotype association mapping in mice identifies a genetic variant in CER1 associated with BMD and fracture in southern Chinese women". Journal of Bone and Mineral Research. 24 (6): 1013–21. doi:10.1359/jbmr.081258. PMID19113921.
Biben C, Stanley E, Fabri L, Kotecha S, Rhinn M, Drinkwater C, Lah M, Wang CC, Nash A, Hilton D, Ang SL, Mohun T, Harvey RP (February 1998). "Murine cerberus homologue mCer-1: a candidate anterior patterning molecule". Developmental Biology. 194 (2): 135–51. doi:10.1006/dbio.1997.8812. PMID9501024.
Young RP, Hopkins RJ, Hay BA, Epton MJ, Mills GD, Black PN, Gardner HD, Sullivan R, Gamble GD (October 2009). "A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers". Postgraduate Medical Journal. 85 (1008): 515–24. doi:10.1136/pgmj.2008.077107. PMID19789190.