Cerberus gene family

Cerberus is a signaling molecule whose main functions include contributing to the formation of the head, and left and right asymmetry. This gene varies slightly from species to species, but its overall functions seem to be similar. 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.[1] Interestingly, Xenopus Cerberus causes a protein to be secreted that is able to induce the formation of an ectopic head.[2] 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.[3] This is why misexpression of Cerberus can cause the heart to fold in the opposite direction during development.[4] When Cerberus is “knocked down” and BMP and Wnt are up regulated the head does not form. Interestingly 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.[5] 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.[6]

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.[7]

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.[8]

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.[9]

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.[10] 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.[11]

References

  1. ↑ De Robertis, E. M.; Piccolo, Stefano; Agius, Eric; Leyns, Luc; Bhattacharyya, Subha; Grunz, Horst; Bouwmeester, Tewis. "http://www.nature.com/doifinder/10.1038/17820". Nature. 397 (6721): 707–710. doi:10.1038/17820. PMC 2323273Freely accessible. PMID 10067895. External link in |title= (help)
  2. ↑ Pearce, Jonathan J. H.; Penny, Graeme; Rossant, Janet (1999-05-01). "A Mouse Cerberus/Dan-Related Gene Family". Developmental Biology. 209 (1): 98–110. doi:10.1006/dbio.1999.9240.
  3. ↑ 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. ISSN 0950-1991. PMID 17507406.
  4. ↑ Zhu, Lei; Marvin, Martha J.; Gardiner, Aaron; Lassar, Andrew B.; Mercola, Mark; Stern, Claudio D.; Levin, Michael (1999-09-09). "Cerberus regulates left–right asymmetry of the embryonic head and heart". Current Biology. 9 (17): 931–938. doi:10.1016/S0960-9822(99)80419-9. ISSN 0960-9822. PMID 10508582.
  5. ↑ Silva, Ana Cristina; Filipe, Mario; Kuerner, Klaus-Michael; Steinbeisser, Herbert; Belo, José António (2003-10-15). "Endogenous Cerberus activity is required for anterior head specification in Xenopus". Development. 130 (20): 4943–4953. doi:10.1242/dev.00705. ISSN 0950-1991. PMID 12952900.
  6. ↑ Belo, Jose; Anna C. Silva; Ana-Cristina Borges; Mario Filipe; Margaret Bento; Lisa Goncalves; Marta Vitorino; Ana-Marisa Salguerio; Vera Texeira; Ana T. Tavares; Sara Marques (14 November 2008). "Generating asymmetries in the early vertebrate embryo: the role of the Cerberus-like family". Int. J. Dev. Biol. (53): 1399–1407. doi:10.1387/ijdb.072297jb. ISSN 1696-3547.
  7. ↑ Silva, A. C.; M. Filipe; K. Kuerner; H. Steinbeisser; J. A. Belo (15 Oct 2003). "Endogenous Cerberus activity is required for anterior head specification in Xenopus". Development. 130 (20): 4943–53. doi:10.1242/dev.00705. PMID 12952900.
  8. ↑ Tavares, A. T.; S. Andrade; A. C. Silvia; J. A. Belo (2007). "Cerberus is a feedback inhibitor of Nodal asymmetric signaling in the chick embryo.". Development. 134 (11): 2051–60. doi:10.1242/dev.000901. PMID 17507406.
  9. ↑ Marszalek, J.; P. Ruiz-lozano; E. Roberts; K. R. Chien; L.S. Goldstein (1999). "Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II.". Proc. Natl. Acad. Sci. U.S.A.: 5043–5048. doi:10.1073/pnas.96.9.5043.
  10. ↑ Foley, A. C.; O. Korol; A. M. Timmer; M. Mercola (1 Mar 2007). "Multiple functions of Cerberus cooperate to induce heart downstream of Nodal". Dev Biol. 303 (1): 57–65. doi:10.1016/j.ydbio.2006.10.033.
  11. ↑ Hashimoto, H.; M. Rebagliata; N. Ahmad; O. Muraoka; T. Kurokawa; M. Hibi; T. Suzuki (15 Apr 2004). "The Cerberus/Dan-family protein Charon is a negative regulator of Nodal signaling during left-right patterning in zebrafish". Development. 131: 1741–53. doi:10.1242/dev.01070.


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