Cerberus (protein)

Last updated
CER1
Identifiers
Aliases CER1 , DAND4, cerberus 1, DAN family BMP antagonist
External IDs OMIM: 603777 MGI: 1201414 HomoloGene: 3983 GeneCards: CER1
Orthologs
SpeciesHumanMouse
Entrez

9350

12622

Ensembl

ENSG00000147869

ENSMUSG00000038192

UniProt

O95813

O55233

RefSeq (mRNA)

NM_005454

NM_009887

RefSeq (protein)

NP_005445

NP_034017

Location (UCSC) Chr 9: 14.72 – 14.72 Mb Chr 4: 82.8 – 82.8 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Cerberus is a protein that in humans is encoded by the CER1 gene. [5] [6] Cerberus is a signaling molecule which contributes to the formation of the head, heart and left-right asymmetry of internal organs. This gene varies slightly from species to species but its overall functions seem to be similar.

Contents

Cerberus is secreted by the anterior visceral endoderm and blocks the action of BMP, Nodal and Wnt, secreted by the primitive node, which allows for the formation of a head region. This is accomplished by inhibiting the formation of mesoderm in this region. [7] Xenopus Cerberus causes a protein to be secreted that is able to induce the formation of an ectopic head. [8] Knockdown experiments have helped to explain Cerberus's role in both the formation of the head and left and right symmetry. These experiments have shown that Cerberus helps to keep Nodal from crossing to the right side of the developing embryo, allowing left and right asymmetry to form. [9] This is why misexpression of Cerberus can cause the heart to fold in the opposite direction during development. [10] When Cerberus is “knocked down” and BMP and Wnt are up regulated the head does not form. Other experiments using mice that this gene has been “knocked out” showed no head defects, which suggest that it is the combination of the up regulation of BMP and Wnt along with the absence of Cerberus that causes this defect. [11] For the heart, Cerberus is one of several factors that inhibits Nodal to initiate cardiomyogenic differentiation [12] [13]

The Cerberus gene family produces many different signal proteins that are antagonistically involved in establishing anterior-posterior patterning and left-right patterning in vertebrate embryos. [14]

Function

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. [15] [16] [7] 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. [17] 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. [5]

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. [18]

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. [11]

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. [7]

Location

It is expressed in the anterior endoderm but can vary dorsally and ventrally between species. For example, in amphibians Cerberus is expressed in the anterior dorsal endoderm and in mice it is expressed in the anterior visceral endoderm. [11]

Anterior-posterior patterning

Anterior-posterior patterning by Cerberus is accomplished by acting as an antagonist to nodal, bmp, and wnt signaling molecules in the anterior region of the vertebrate embryo during gastrulation. Knock down experiments in which Cerberus was partially repressed show a decreased formation of the head structures. In experiments where Cerberus was decreased and wnt, bmp and nodal signals were increased, embryos completely lacked head structures and develop only trunk structures. These experiments suggest that a balance of these signaling molecules is required for proper development of the anterior and posterior regions. [9]

Left-right asymmetry

Cerberus is also involved in establishing left-right asymmetry that is critical to the normal physiology of a vertebrate. By blocking nodal in the right side of the embryo, concentrations of nodal remain high only in the left side of the embryo and the nodal cascade cannot be activated in the right side. Because left-right asymmetry is so vital, Cerberus works along with the nodal cilia that push left-determining signal molecules to the left side of the embryo to ensure that the left-right axis is correctly established. Misexpression experiments show that lack of Cerberus expression on the right side can result in situs inversus and cardiovascular malformations. [19]

Heart development

Cerberus plays a vital role in heart development and differentiation of cardiac mesoderm through activation of Nodal signaling molecule. Nodal and Wnt activity is antagonized in the endoderm which results in diffusible signals from Cerberus. More specifically, Nodal inhibits certain cells from joining cardiogenesis while simultaneously activating cells. The cells that respond to Nodal produce Cerberus in the underlying endoderm which causes heart development in adjacent cells. Knockdown experiments of Cerberus reduced endogenous cardiomyogenesis and ectopic heart induction. [12] Block of Nodal leads to induction of cardiogenic genes through chromatin remodeling. [13] The heart is developed asymmetrically using the left-right patterning induced by Cerberus which creates a higher concentration of signaling molecules on the left side. Experiments that inhibited Cerberus led to a loss of left-right polarity of the heart, which was shown by bilateral expression of left side-specific genes. [20]

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/SNF chromatin 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. [13] Targeted inactivation of another homologue, Cerberus like-2 (Cerl2), in the mouse leads to left ventricular cardiac hyperplasia and systolic dysfunction. [21]

Evolutionary role and conservation

The Nodal signaling pathway, including Cerberus, is evolutionary conserved. It is theorized that the gut was the first asymmetrical organ to develop, but in modern vertebrates, most internal organs display asymmetry. While the Nodal pathway is found in deuterostomes and protostomes, a proposed common ancestor called Urbilateria has been theorized to be the progenitor of all bilaterally symmetrical animals. [22] The only protostomes to possess Nodal are mollusks (including snails), while the vast majority of deuterostomes possess this signaling pathway. [23] Cerberus is present in the signaling pathway of amphioxus, an early chordate. [24] As a result, it is likely that the majority of vertebrates possess Cerberus or analogous molecules (such as Coco in frogs, Dand5 in mice, and charon in zebrafish). [23] Notably, chickens lack the ciliary dependent mechanisms of Nodal distribution, but Nodal and Cerberus are still an integral part of their asymmetrical L-R development. [25] Pigs also lack this ciliary mechanism, but both species rely on an ion pump to accomplish L-R distribution of Nodal. [23] Cerberus's (and analogous molecules') role in this pathway is to bind to Nodal in an inhibitory manner.

Related Research Articles

<span class="mw-page-title-main">Gastrulation</span> Stage in embryonic development in which germ layers form

Gastrulation is the stage in the early embryonic development of most animals, during which the blastula, or in mammals the blastocyst, is reorganized into a two-layered or three-layered embryo known as the gastrula. Before gastrulation, the embryo is a continuous epithelial sheet of cells; by the end of gastrulation, the embryo has begun differentiation to establish distinct cell lineages, set up the basic axes of the body, and internalized one or more cell types including the prospective gut.

<span class="mw-page-title-main">Somitogenesis</span>

Somitogenesis is the process by which somites form. Somites are bilaterally paired blocks of paraxial mesoderm that form along the anterior-posterior axis of the developing embryo in segmented animals. In vertebrates, somites give rise to skeletal muscle, cartilage, tendons, endothelium, and dermis.

The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling pathways use either nearby cell-cell communication (paracrine) or same-cell communication (autocrine). They are highly evolutionarily conserved in animals, which means they are similar across animal species from fruit flies to humans.

<span class="mw-page-title-main">Primitive streak</span> Structure in early amniote embryogenesis

The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians, the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the broad end towards the anterior, and the narrower region projected to the posterior. The primitive streak forms a longitudinal midline structure in the narrower posterior (caudal) region of the developing embryo on its dorsal side. At first formation, the primitive streak extends for half the length of the embryo. In the human embryo, this appears by stage 6, about 17 days.

<span class="mw-page-title-main">Intermediate mesoderm</span> Layer of cells in mammalian embryos

Intermediate mesoderm or intermediate mesenchyme is a narrow section of the mesoderm located between the paraxial mesoderm and the lateral plate of the developing embryo. The intermediate mesoderm develops into vital parts of the urogenital system.

The transforming growth factor beta (TGFB) signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, cell migration, apoptosis, cellular homeostasis and other cellular functions. The TGFB signaling pathways are conserved. In spite of the wide range of cellular processes that the TGFβ signaling pathway regulates, the process is relatively simple. TGFβ superfamily ligands bind to a type II receptor, which recruits and phosphorylates a type I receptor. The type I receptor then phosphorylates receptor-regulated SMADs (R-SMADs) which can now bind the coSMAD SMAD4. R-SMAD/coSMAD complexes accumulate in the nucleus where they act as transcription factors and participate in the regulation of target gene expression.

Chordin is a protein with a prominent role in dorsal–ventral patterning during early embryonic development. In humans it is encoded for by the CHRD gene.

Lefty are a class of proteins that are closely related members of the TGF-beta superfamily of growth factors. These proteins are secreted and play a role in left-right asymmetry determination of organ systems during development. Mutations of the genes encoding these proteins have been associated with left-right axis malformations, particularly in the heart and lungs.

The heart is the first functional organ in a vertebrate embryo. There are 5 stages to heart development.

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<span class="mw-page-title-main">Cripto</span> Protein-coding gene in the species Homo sapiens

Cripto is an EGF-CFC or epidermal growth factor-CFC, which is encoded by the Cryptic family 1 gene. Cryptic family protein 1B is a protein that in humans is encoded by the CFC1B gene. Cryptic family protein 1B acts as a receptor for the TGF beta signaling pathway. It has been associated with the translation of an extracellular protein for this pathway. The extracellular protein which Cripto encodes plays a crucial role in the development of left and right division of symmetry.

<span class="mw-page-title-main">GDF3</span> Protein-coding gene in humans

Growth differentiation factor-3 (GDF3), also known as Vg-related gene 2 (Vgr-2) is protein that in humans is encoded by the GDF3 gene. GDF3 belongs to the transforming growth factor beta (TGF-β) superfamily. It has high similarity to other TGF-β superfamily members including Vg1 and GDF1.

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<span class="mw-page-title-main">ZIC3</span> Protein-coding gene in the species Homo sapiens

ZIC3 is a member of the Zinc finger of the cerebellum (ZIC) protein family.

<span class="mw-page-title-main">Nodal homolog</span> Mammalian protein found in Homo sapiens

Nodal homolog is a secretory protein that in humans is encoded by the NODAL gene which is located on chromosome 10q22.1. It belongs to the transforming growth factor beta superfamily. Like many other members of this superfamily it is involved in cell differentiation in early embryogenesis, playing a key role in signal transfer from the primitive node, in the anterior primitive streak, to lateral plate mesoderm (LPM).

The Nodal signaling pathway is a signal transduction pathway important in regional and cellular differentiation during embryonic development.

<span class="mw-page-title-main">Ectoderm specification</span> Stage in embryonic development

In Xenopus laevis, the specification of the three germ layers occurs at the blastula stage. Great efforts have been made to determine the factors that specify the endoderm and mesoderm. On the other hand, only a few examples of genes that are required for ectoderm specification have been described in the last decade. The first molecule identified to be required for the specification of ectoderm was the ubiquitin ligase Ectodermin ; later, it was found that the deubiquitinating enzyme, FAM/USP9x, is able to overcome the effects of ubiquitination made by Ectodermin in Smad4. Two transcription factors have been proposed to control gene expression of ectodermal specific genes: POU91/Oct3/4 and FoxIe1/Xema. A new factor specific for the ectoderm, XFDL156, has shown to be essential for suppression of mesoderm differentiation from pluripotent cells.

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References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000038192 - 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. 1 2 "Entrez Gene: CER1".
  6. ↑ 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. PMID   10049596.
  7. 1 2 3 Piccolo S, Agius E, Leyns L, Bhattacharyya S, Grunz H, Bouwmeester T, De Robertis EM (February 1999). "The head inducer Cerberus is a multifunctional antagonist of Nodal, BMP and Wnt signals". Nature. 397 (6721): 707–10. Bibcode:1999Natur.397..707P. doi:10.1038/17820. PMC   2323273 . PMID   10067895.
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  9. 1 2 Tavares AT, Andrade S, Silva AC, Belo JA (June 2007). "Cerberus is a feedback inhibitor of Nodal asymmetric signaling in the chick embryo". Development. 134 (11): 2051–60. doi: 10.1242/dev.000901 . hdl: 10400.1/11578 . PMID   17507406.
  10. ↑ Zhu L, Marvin MJ, Gardiner A, Lassar AB, Mercola M, Stern CD, Levin M (September 1999). "Cerberus regulates left-right asymmetry of the embryonic head and heart". Current Biology. 9 (17): 931–8. doi: 10.1016/S0960-9822(99)80419-9 . PMID   10508582. S2CID   11319206.
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  12. 1 2 Foley AC, Korol O, Timmer AM, Mercola M (March 2007). "Multiple functions of Cerberus cooperate to induce heart downstream of Nodal". Developmental Biology. 303 (1): 57–65. doi:10.1016/j.ydbio.2006.10.033. PMC   1855199 . PMID   17123501.
  13. 1 2 3 Cai W, Albini S, Wei K, Willems E, Guzzo RM, Tsuda M, Giordani L, Spiering S, Kurian L, Yeo GW, Puri PL, Mercola M (November 2013). "Coordinate Nodal and BMP inhibition directs Baf60c-dependent cardiomyocyte commitment". Genes & Development. 27 (21): 2332–44. doi:10.1101/gad.225144.113. PMC   3828519 . PMID   24186978.
  14. ↑ Belo JA, Silva AC, Borges AC, Filipe M, Bento M, Gonçalves L, Vitorino M, Salgueiro AM, Texeira V, Tavares AT, Marques S (14 November 2008). "Generating asymmetries in the early vertebrate embryo: the role of the Cerberus-like family". The International Journal of Developmental Biology. 53 (8–10): 1399–407. doi: 10.1387/ijdb.072297jb . hdl: 10400.1/12103 . PMID   19247954.
  15. ↑ Foley AC, Korol O, Timmer AM, Mercola M (March 2007). "Multiple functions of Cerberus cooperate to induce heart downstream of Nodal". Developmental Biology. 303 (1): 57–65. doi:10.1016/j.ydbio.2006.10.033. PMC   1855199 . PMID   17123501.
  16. ↑ Schneider VA, Mercola M (August 1999). "Spatially distinct head and heart inducers within the Xenopus organizer region". Current Biology. 9 (15): 800–9. doi: 10.1016/S0960-9822(99)80363-7 . PMID   10469564. S2CID   16744197.
  17. ↑ 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. Bibcode:1996Natur.382..595B. doi:10.1038/382595a0. PMID   8757128. S2CID   4361202.
  18. ↑ 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 . PMID   16596263.
  19. ↑ Friedberg I (September 1977). "The effect of ionophores on phosphate and arsenate transport in Micrococcus lysodeikticus". FEBS Letters. 81 (2): 264–6. doi:10.1016/0014-5793(77)80531-0. PMID   21813. S2CID   32783955.
  20. ↑ Hashimoto H, Rebagliati M, Ahmad N, Muraoka O, Kurokawa T, Hibi M, Suzuki T (April 2004). "The Cerberus/Dan-family protein Charon is a negative regulator of Nodal signaling during left-right patterning in zebrafish". Development. 131 (8): 1741–53. doi: 10.1242/dev.01070 . PMID   15084459.
  21. ↑ Araújo AC, Marques S, Belo JA (2014). "Targeted inactivation of Cerberus like-2 leads to left ventricular cardiac hyperplasia and systolic dysfunction in the mouse". PLOS ONE. 9 (7): e102716. Bibcode:2014PLoSO...9j2716A. doi: 10.1371/journal.pone.0102716 . PMC   4102536 . PMID   25033293.
  22. ↑ De Robertis, E. M.; Sasai, Y. (1996-03-07). "A common plan for dorsoventral patterning in Bilateria". Nature. 380 (6569): 37–40. Bibcode:1996Natur.380...37D. doi:10.1038/380037a0. ISSN   0028-0836. PMID   8598900. S2CID   4355458.
  23. 1 2 3 Blum, Martin; Feistel, Kerstin; Thumberger, Thomas; Schweickert, Axel (2014-04-15). "The evolution and conservation of left-right patterning mechanisms". Development. 141 (8): 1603–1613. doi: 10.1242/dev.100560 . ISSN   0950-1991. PMID   24715452.
  24. ↑ Li, Guang; Liu, Xian; Xing, Chaofan; Zhang, Huayang; Shimeld, Sebastian M.; Wang, Yiquan (2017-04-04). "Cerberus–Nodal–Lefty–Pitx signaling cascade controls left–right asymmetry in amphioxus". Proceedings of the National Academy of Sciences of the United States of America. 114 (14): 3684–3689. doi: 10.1073/pnas.1620519114 . ISSN   0027-8424. PMC   5389317 . PMID   28320954.
  25. ↑ Tavares, Ana Teresa; Andrade, Sofia; Silva, Ana Cristina; Belo, José António (2007-06-01). "Cerberus is a feedback inhibitor of Nodal asymmetric signaling in the chick embryo". Development. 134 (11): 2051–2060. doi: 10.1242/dev.000901 . hdl: 10400.1/11578 . ISSN   0950-1991. PMID   17507406.

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