Specific structure and unique function define the hemicentin
© Xu et al.; licensee BioMed Central Ltd. 2013
Received: 14 December 2012
Accepted: 24 April 2013
Published: 26 June 2013
Hemicentin has come a long way from when it was first identified in C. elegans as him-4 (High incidence of males). The protein is now a recognized player in maintaining the architectural integrity of vertebrate tissues and organs. Highly conserved hemicentin sequences across species indicate this gene’s ancient evolutionary roots and functional importance. In mouse, hemicentin is liberally distributed on the cell surface of many cell types, including epithelial cells, endothelial cells of the eye, lung, and uterus, and trophectodermal cells of blastocyst. Recent discoveries have uncovered yet another vital purpose of hemicentin 1. The protein also serves a unique function in mitotic cytokinesis, during which this extracellular matrix protein plays a key role in cleavage furrow maturation. Though understanding of hemicentin function has improved through new discoveries, much about this protein remains mysterious.
KeywordsExtracellular matrix (ECM) Fibulin Hemicentin Embryogenesis Tissue/Organ architecture Cell division Mitosis
In the last two decades fibulins were rapidly recognized as a family of glycoproteins consisting of 6 or 8 members, fibulin-1, -2, -3, -4, -5, -7, and fibulin-6 and fibulin-8. Fibulin-6 and −8 are also referred to as hemicentin-1 and hemicentin-2, respectively . Fibulins are defined as proteins consisting of a series of epidermal growth factor (EGF)-like modules, followed by a carboxyl-terminal fibulin-type module. Under this definition, 5 proteins (fibulin-1, -2, -3, -4, -5) were traditionally categorized into this family with the more recent addition of fibulin-7 . Hemicentin-1(hem-1/fibl-6) and hemicentin-2 (fibl-8) were qualified for this family as well [1, 3]. However, recent research identifying a function unique to hemicentin and a novel domain at its amino acid terminal have distinguished hemicentin from the fibulin family.
Hemicentin was first named in C. elegans as him-4 (short for High incidence of males) and is aptly one of genes responsible for increased X chromosome loss in nematodes [4–6]. Two orthologs discovered in vertebrate animals were subsequently termed hemicentin-1 and hemincentin-2. These molecules are characterized by a vWA (von Willebrand/Integrin A) domain attached to the amino acid-terminal of the signal peptide and hemicentin motif (hem motif) followed by approximately fifty Ig (immunoglobulin) modules. The vWA domain and Ig module together take up > 80% of the molecular structure and are responsible for predicting the function of hem on hemidesmosomes . Thus, although hemicentin fit the criteria for fibulin, structural differences from the rest of the fibulin family members support treating them as an independent protein family. Recent findings on hemicentin’s unique function in the cell cycle have served to strengthen this fact [7–11].
When a 90-kDa calcium-binding secreted glycoprotein was termed the first fibulin, this extracellular matrix (ECM) protein was known to function within fibrillar basement membrane and independently as a BM-90 [12–14]. The second family member, fibulin-2, was identified shortly thereafter . Then S1-5/EFEMP1, BMP1/EFEMP2/H411, DANCE/EVEC/UP50 and TM-14 were also merged into the fibulin family as fibulin-3, -4, -5 and −7, respectively [2, 3, 16–18]. These proteins were arranged in the fibulin family by categorizing the secondary structures of fibulin-type and EGF-like modules found at their carboxy-terminals.
Hemicentin nomenclature in model animals
Translation length (AA)
vWA and Ig
Hemicentin Fibulin6 Him-4
Chromosome X: 9,717,568-9,753,706
Chromosome 20: 34,182,641-34,317,215
Chromosome 8: 33,554,295
Scaffold GL172705.1: 1,652,334-1,775,760
Scaffold GL172827.1: 1,836,154-1,900,680
Hemicentin 1 Fibulin6
Chromosome 1: 152,410,657-152,840,181
Hemicentin 2 Fibulin8
Chromosome 2: 31,169,935-31,316,258
Chromosome 1: 185,703,683-186,160,081
Chromosome 9: 133,028,269-133,309,510
Previous review articles based on hereditary disease studies and basic research results gathered from animal models, demonstrated the various functions of fibulins in human disorders [3, 18–20]. Recent progresses discerning the function of hemicentin in various animal models have drawn increasing attention.
Histological and histochemical analyses in C. elegans, mouse, and zebra fish models suggest hemicentin functions as an extracellular adhesive, forming cell-cell and cell-basement membrane adhesion that hold cells together and maintain tissue and organ integrity [6, 7, 21]. In C. elegans, hemicentin forms linear structures between somatic cells to anchor the epidermis to the uterus, the mechanosensory neurons, and the intestine. The protein also assembles an elastic, fiber-like structure which surrounds the nematode body-wall muscles [6, 22]. In mouse, hemicentin assembles into closed sheets that are insinuated between cells. This structure completely surrounds cells in certain tissues, such as dermal epithelial cells, stratified corneal epithelial cells, and tongue epithelial cells . Hemicentin is also distributed across the entire inside surface of the lens. In the retina, hemicentin assembles on the pigmented retina epithelium and choroid basement membranes to form cell-ECM-cell “sandwiches” that flank collagen XVIII in Bruch’s membrane . Mutations in hem-1 have been linked to age related macular degeneration (ARMD), indicating the importance of this protein in retinal function  and providing a new avenue for understanding ARMD, the main cause of blindness in the western world.
In mouse embryonic development, hemicentin is co-localized with desmosomal cadherin desmocollin-3 on the periphery of blastocytic trophectoderm cells originating from the first differentiation after fertilization and oocyte formation. This peripheral distribution is observed as a punctuated linear structure during morula stage. Before this stage, the proteins are first observed on the embryonic cell surface of four to six cell stages, when each cell is still totipotent. The protein’s distribution in cells of earlier embryonic stages remains unclear . Interestingly, genetic analyses on four-cell stage mouse embryo have recently unveiled a distinctive function of hemicentin in mitotic cytokinesis .
In hemicentin-1 deficient mice, embryonic cells cannot complete mitotic cytokinesis to form daughter cells. These cells can, however, complete the preceding elements of mitosis. Thus, the majority of mutant blastomeres arrest at the one-cell or two-cell stage with multiple nuclei, indicating the number of attempted mitosis and incomplete cytokinetic cleavage furrow retractions . The loss of hemicentin leading to multinucleate cells was previously observed in C. elegans germ lines and was concluded to be the result of “occasional fusion of neighboring cells” . However, recent studies have shown that the multinucleate cells found in mouse pre-implantation blastomeres are caused by hemicentin-1 defects, and suggesting that the previously disclaimed observations in C. elegans may be due to hem-1 defects as well. The study in mouse used three different methods to delete HMCN1, homogenous recombination, RNAi HMCN1 knockdown, and induced parthenogenesis on HMCN1+/−, which all resulted in arrested blastomeres with multiple nuclei. The genetic manipulations and resultant multinuclear blastomeric findings indicate that the “fused cells” found in C. elegans are actually the result of HMCN1 defects introduced in the study . Recently, zebrafish hem-1/fibl-6 and hem-2/fibl-8 were reported to be highly connected to epidermal-dermal development in relation to adjacent basement membrane [21, 24]. HMCN1 has been proven to be one of the genes related to fin basement malformation, characterized as Fraser syndrome . Double knock-down defects of HMCN2 and FBLN1 (but not HMCN2 alone) proved that both genes are crucial for epidermal–dermal junction formation and fin mesenchymal cell migration during zebrafish development . The diverse functions of the hemicentin on various developmental stages of both invertebrates and vertebrates from cell division to tissue/organ architecture indicate conserved functioning of the ancient genes.
Loss of hemicentin-1 causes acytokinetic cell divisions in mouse early development, a recently discovered novel function for this extracellular matrix protein. This function distinguishes hemicentin from other ECM families, including the fibulin family to which it was previously categorized. In addition to calling into question protein nomenclature, this finding evokes many new questions on the function of this ECM protein in cell cycle. What is the membrane receptor(s) which link hemicentin to the internal cytoskeletal structure? What are differences in hemicentin found on the contractile ring complex at mitotic status and G0 stage? Does hemicentin play a role in promoting cell differentiation and tissue architecture? If so, what are their receptors or trans-membrane protein players? Many questions regarding the hemicentin protein family remain unresolved and waiting for investigation.
In this review, no any experimental research carried out on humans or human tissues /cells.
This work is supported by Shaanxi NSF fund for Key Innovational Research, Central Universities Research Fund (GK201301001), US MD Stem Cell Research Fund (TEDCO, 2009-MSCRFE-0083-00) and American Heart Association (0120673Z) to Dr. X Xu.
- Colley MA, et al: Fibulins. The extracellular matrix an overview. Edited by: Mecham RP. 2011, 337-367. Berlin Heiderberg: Springer Verlag.View ArticleGoogle Scholar
- de Vega S, et al: TM14 is a new member of the fibulin family (fibulin-7) that interacts with extracellular matrix molecules and is active for cell binding. J Biol Chem. 2007, 282 (42): 30878-30888. 10.1074/jbc.M705847200View ArticlePubMedGoogle Scholar
- Argraves WS, et al: Fibulins: physiological and disease perspectives. EMBO Rep. 2003, 4 (12): 1127-1131. 10.1038/sj.embor.7400033PubMed CentralView ArticlePubMedGoogle Scholar
- Hutter H, et al: Conservation and novelty in the evolution of cell adhesion and extracellular matrix genes. Science. 2000, 287 (5455): 989-994. 10.1126/science.287.5455.989View ArticlePubMedGoogle Scholar
- C. elegans Sequencing Consortium: Genome sequence of the nematode C. elegans: a platform for investigating biology. Science. 1998, 282 (5396): 2012-2018.View ArticleGoogle Scholar
- Vogel BE, et al: Hemicentin, a conserved extracellular member of the immune-globulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions. Development. 2001, 128 (6): 883-894.PubMedGoogle Scholar
- Xu X, et al: A secreted protein promotes cleavage furrow maturation during cytokinesis. Curr Biol. 2011, 21 (2): 114-119. 10.1016/j.cub.2010.12.006PubMed CentralView ArticlePubMedGoogle Scholar
- Jordan SN, et al: Cytokinesis: thinking outside the cell. Curr Biol. 2011, 21 (3): R119-R121. 10.1016/j.cub.2010.12.040View ArticlePubMedGoogle Scholar
- Xu X, et al: A new job for ancient extracellular matrix proteins: Hemicentins stabilize cleavage furrows. Commun Integr Biol. 2011, 4 (4): 433-435.PubMed CentralView ArticlePubMedGoogle Scholar
- Vogel BE, et al: Hemicentins: what have we learned from worms?. Cell Res. 2006, 16 (11): 872-878. 10.1038/sj.cr.7310100View ArticlePubMedGoogle Scholar
- Grabt RP: Control from without. The Scientist. 2011,http://www.the-scientist.com/?articles.view/articleNo/30509/title/Control-from-Without/, Google Scholar
- Argraves WS, et al: Fibulin, a novel protein that interacts with the fibronectin receptor beta subunit cytoplasmic domain. Cell. 1989, 58 (4): 623-629. 10.1016/0092-8674(89)90097-4View ArticlePubMedGoogle Scholar
- Argraves WS, et al: Fibulin is an extracellular matrix and plasma glycoprotein with repeated domain structure. J Cell Biol. 1990, 111 (6 Pt 2): 3155-3164.View ArticlePubMedGoogle Scholar
- Kluge M, et al: Characterization of a novel calcium-binding 90-kDa glycoprotein (BM-90) shared by basement membranes and serum. Eur J Biochem. 1990, 193 (3): 651-659. 10.1111/j.1432-1033.1990.tb19383.xView ArticlePubMedGoogle Scholar
- Pan TC, et al: Sequence of extracellular mouse protein BM-90/fibulin and its calcium-dependent binding to other basement-membrane ligands. Eur J Biochem. 1993, 215 (3): 733-740. 10.1111/j.1432-1033.1993.tb18086.xView ArticlePubMedGoogle Scholar
- Tran H, et al: The self-association and fibronectin-binding sites of fibulin-1 map to calcium-binding epidermal growth factor-like domains. J Bio Chem. 1997, 272 (36): 22600-22606. 10.1074/jbc.272.36.22600. 10.1074/jbc.272.36.22600View ArticleGoogle Scholar
- Gallagher WM, et al: MBP1: a novel mutant p53-specific protein partner with oncogenic properties. Oncogene. 1999, 18 (24): 3608-3616. 10.1038/sj.onc.1202937View ArticlePubMedGoogle Scholar
- Timpl R, et al: Fibulins: a versatile family of extracellular matrix proteins. Nat Rev Mol Cell Biol. 2003, 4 (6): 479-489. 10.1038/nrm1130View ArticlePubMedGoogle Scholar
- de Vega S, et al: Fibulins: multiple roles in matrix structures and tissue functions. Cell Mol Life Sci. 2009, 66 (11–12): 1890-1902.View ArticlePubMedGoogle Scholar
- Segade F: Molecular evolution of the fibulins: implications on the functionality of the elastic fibulins. Gene. 2010, 464 (1–2): 17-31.View ArticlePubMedGoogle Scholar
- Carney TJ, et al: Genetic analysis of fin development in zebrafish identifies furin and hemicentin1 as potential novel Fraser syndrome disease genes. PLoS Genet. 2010, 6: e1000907. 10.1371/journal.pgen.1000907PubMed CentralView ArticlePubMedGoogle Scholar
- Muriel JM, et al: Fibulin-1C and Fibulin-1D splice variants have distinct functions and assemble in a hemicentin-dependent manner. Development. 2005, 132: 4223-4234. 10.1242/dev.02007View ArticlePubMedGoogle Scholar
- Xu X, et al: Hemicentins assemble on diverse epithelia in the mouse. J Histochem Cytochem. 2007, 55 (2): 119-126.View ArticlePubMedGoogle Scholar
- Feitosa NM, et al: Hemicentin 2 and Fibulin 1 are required for epidermal-dermal junction formation and fin mesenchymal cell migration during zebrafish development. Dev Biol. 2012, 369 (2): 235-248. 10.1016/j.ydbio.2012.06.023PubMed CentralView ArticlePubMedGoogle Scholar
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