IFITM1-Mediated Cell Repulsion Controls the Initial Steps of Germ Cell Migration in the Mouse
2005; Elsevier BV; Volume: 9; Issue: 6 Linguagem: Inglês
10.1016/j.devcel.2005.11.009
ISSN1878-1551
Autores Tópico(s)interferon and immune responses
ResumoIn this issue of Developmental Cell, a novel mechanism for the initiation of germ cell migration in the mouse has been identified, based upon differential expression of interferon-inducible transmembrane proteins in the gastrula (Tanaka et al., 2005Tanaka S.S. Yamaguchi Y.L. Tsoi B. Lickert H. Tam P.P.L. Dev. Cell. 2005; 9: 745-756Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). Germ cells are displaced by a repulsion mechanism from the posterior mesoderm into the endoderm. In this issue of Developmental Cell, a novel mechanism for the initiation of germ cell migration in the mouse has been identified, based upon differential expression of interferon-inducible transmembrane proteins in the gastrula (Tanaka et al., 2005Tanaka S.S. Yamaguchi Y.L. Tsoi B. Lickert H. Tam P.P.L. Dev. Cell. 2005; 9: 745-756Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). Germ cells are displaced by a repulsion mechanism from the posterior mesoderm into the endoderm. IFITMs (interferon-inducible transmembrane proteins) are a family of related cell surface proteins originally identified as targets of interferon stimulation in neuroblastoma cells. Three members of the Ifitm family (1–3) are closely clustered in the genome (on chromosome 7 in the mouse, 11 in the human). Human IFITM1 protein has been implicated in homotypic cell adhesion of leukemic B cells (Evans et al., 1990Evans S.S. Lee D.B. Han T. Tomasi T.B. Evans R.L. Blood. 1990; 76: 2583-2593Crossref PubMed Google Scholar). These proteins first appeared on the radar screens of those studying germ cells when two separate investigations revealed that mouse Iftm3 is expressed in the germ cells during gastrulation (Saitou et al., 2002Saitou M. Barton S.C. Surani M.A. Nature. 2002; 418: 293-300Crossref PubMed Scopus (689) Google Scholar, Tanaka and Matsui, 2002Tanaka S.S. Matsui Y. Mech. Dev. 2002; 119: S261-S267Crossref PubMed Scopus (73) Google Scholar), precisely at the time when germ cells are becoming specified in the mouse (Lawson and Hage, 1994Lawson K.A. Hage W.J. Ciba Found. Symp. 1994; 182: 68-84PubMed Google Scholar). The way germ cells become specified and how their initial behavior is controlled are poorly understood. Lineage analysis showed that they first appear in the proximal epiblast (Lawson and Hage, 1994Lawson K.A. Hage W.J. Ciba Found. Symp. 1994; 182: 68-84PubMed Google Scholar) and move to the posterior region of the primitive streak and the base of the allantois (Ginsburg et al., 1990Ginsburg M. Snow M.H. McLaren A. Development. 1990; 110: 521-528PubMed Google Scholar). Germ cells spread from this region into surrounding structures, including the posterior embryonic endoderm, the extraembryonic endoderm, and the allantois (Anderson et al., 2000Anderson R. Copeland T.K. Scholer H. Heasman J. Wylie C. Mech. Dev. 2000; 91: 61-68Crossref PubMed Scopus (227) Google Scholar). Germ cells that move into the posterior endoderm are motile, but are retained there as it forms the hind-gut (Molyneaux et al., 2001Molyneaux K.A. Stallock J. Schaible K. Wylie C. Dev. Biol. 2001; 240: 488-498Crossref PubMed Scopus (227) Google Scholar), before subsequently migrating to the genital ridges. The mechanisms by which germ cells move from the posterior primitive streak region into the endoderm, localize to the region that will form the hind-gut, and then remain there are currently unknown. Some light has been thrown on this process by the work of Tanaka and colleagues, who report their findings in this issue of Developmental Cell (Tanaka et al., 2005Tanaka S.S. Yamaguchi Y.L. Tsoi B. Lickert H. Tam P.P.L. Dev. Cell. 2005; 9: 745-756Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). Careful in situ hybridizations reported in this and in earlier publications (Lange et al., 2003Lange U.C. Saitou M. Western P.S. Barton S.C. Surani M.A. BMC Dev. Biol. 2003; 3: 1Crossref PubMed Scopus (111) Google Scholar, Saitou et al., 2002Saitou M. Barton S.C. Surani M.A. Nature. 2002; 418: 293-300Crossref PubMed Scopus (689) Google Scholar, Tanaka and Matsui, 2002Tanaka S.S. Matsui Y. Mech. Dev. 2002; 119: S261-S267Crossref PubMed Scopus (73) Google Scholar, Tanaka et al., 2004Tanaka S.S. Nagamatsu G. Tokitake Y. Kasa M. Tam P.P. Matsui Y. Dev. Dyn. 2004; 230: 651-659Crossref PubMed Scopus (61) Google Scholar) show that Ifitm1-3 expression is highly dynamic during gastrulation. As previously reported, Ifitm3 is expressed first, in the proximal epiblast where germ cells arise. Subsequently, Ifitm1 comes on in the proximal epiblast, followed by Ifitm2, which is expressed more widely. Ifitm3 expression is a downstream target of BMP signaling (Saitou et al., 2002Saitou M. Barton S.C. Surani M.A. Nature. 2002; 418: 293-300Crossref PubMed Scopus (689) Google Scholar), which is required for germ cell formation in the mouse. Of particular interest are the subsequent changes in expression of Ifitm1 and -3. Ifitm3 becomes restricted in its expression to the germ cell precursors in the posterior primitive streak region, while Ifitm1 is expressed by both germ cells and posterior mesoderm cells. The germ cells then turn off Ifitm1 as they leave this region and enter the endoderm. For a schema of this complex expression pattern, see Figure 7 of Tanaka et al., 2005Tanaka S.S. Yamaguchi Y.L. Tsoi B. Lickert H. Tam P.P.L. Dev. Cell. 2005; 9: 745-756Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar. This changing pattern of expression, coupled to previous evidence that IFITMs may mediate homotypic cell adhesion, suggested a possible role in germ cell movement from the mesoderm into the posterior embryonic endoderm. The evidence presented by Tanaka and colleagues suggests that Ifitm1 and 3 control a repulsion mechanism. When both proteins are being expressed by the germ cells, there is no effect. However, the turning off of Ifitm1 by the Ifitm3-expressing germ cells causes them to be repelled by their neighbors that continue to express Ifitm1 in the posterior primitive streak region (Figure 7 in Tanaka et al., 2005Tanaka S.S. Yamaguchi Y.L. Tsoi B. Lickert H. Tam P.P.L. Dev. Cell. 2005; 9: 745-756Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). Two elegant experiments are provided as primary evidence for this hypothesis. First, Ifitm1 was ectopically expressed, by transfection, in the endoderm. In the mosaic of Ifitm1-expressing and nonexpressing endodermal cells thus generated, the germ cells always avoided the regions of Ifitm1 expression. This repulsive behavior was retained throughout hind-gut formation. When Ifitm1 and -3 were coexpressed in the endoderm, germ cells did not avoid areas of coexpression, suggesting that the repulsive effect of Ifitm1 is only exerted when germ cells turn it off. Second, loss of function data is provided by RNAi-mediated silencing of Ifitm1, which caused germ cells to remain in the mesoderm instead of migrating into the endoderm. This suggests that the normal role of Ifitm1 in the mesoderm is to cause the germ cells to move into the endoderm. Importantly, none of these treatments altered overall germ cell numbers, thus excluding cell specification, death, and proliferation as primary targets of IFITMs in these experiments. Both chemoattraction and repulsion are already known to be important components of germ cell migration in several species. The importance of this new work is that it addresses the earliest stage in the migratory process, about which nothing is currently known, and identifies a novel mechanism. It also offers a potential explanation of a later event. At E9.0 in the mouse, time-lapse movie analysis shows that germ cells are highly motile, but cannot escape from the hind-gut (Molyneaux et al., 2001Molyneaux K.A. Stallock J. Schaible K. Wylie C. Dev. Biol. 2001; 240: 488-498Crossref PubMed Scopus (227) Google Scholar). Since expression of Ifitm1 continues in the mesoderm surrounding the gut, then Ifitm1-mediated repulsion might serve to cage the germ cells in this particular region until the genital ridges, the targets of the migrating germ cells, have formed. Potentially, signals from the genital ridges would downregulate this repulsion mechanism locally and allow the germ cells to migrate out of the gut. There is still much to do before a full mechanistic explanation is established. One result presented in the paper does not fit particularly well with a simple cell-repulsion mechanism. Ectopic expression of Ifitm3 in endoderm cells caused them to accumulate posteriorly, in the region occupied by the germ cells. These cells are already in the endoderm, so are not being moved to the germ cell region by simple repulsion by the mesoderm. This result suggests that Ifitm3 may play another role in germ cell behavior, which localizes germ cells within the endoderm. If so, does it also play a role in the exit from the endoderm, or is this mediated entirely by Ifitm1-mediated repulsion? Loss-of-function analysis of Ifitm3 is badly needed, as is a mechanistic explanation for IFITM function(s) in these processes.
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