I just know that Lgr5 is not the only orphan G protein coupled receptor that could mark stem cell population. There is a Lgr6 positive stem cells. There is another Lgr4 gene as well. Lgr4, Lgr5 and Lgr6, all are close related leucine-rich repeat-containing heterotrimeric guanine nucleotide-binding protein coupled receptors! They are markers, what's next?
Science 12 March 2010:
Vol. 327. no. 5971, pp. 1385 - 1389
DOI: 10.1126/science.1184733Lgr6 Marks Stem Cells in the Hair Follicle That Generate All Cell Lineages of the Skin
Hugo J. Snippert,1,* Andrea Haegebarth,1,* Maria Kasper,2 Viljar Jaks,2 Johan H. van Es,1 Nick Barker,1 Marc van de Wetering,1 Maaike van den Born,1 Harry Begthel,1 Robert G. Vries,1 Daniel E. Stange,1 Rune Toftgård,2 Hans Clevers,1
Mammalian epidermis consists of three self-renewing compartments: the hair follicle, the sebaceous gland, and the interfollicular epidermis. We generated knock-in alleles of murine Lgr6, a close relative of the Lgr5 stem cell gene. Lgr6 was expressed in the earliest embryonic hair placodes. In adult hair follicles, Lgr6+ cells resided in a previously uncharacterized region directly above the follicle bulge. They expressed none of the known bulge stem cell markers. Prenatal Lgr6+ cells established the hair follicle, sebaceous gland, and interfollicular epidermis. Postnatally, Lgr6+ cells generated sebaceous gland and interfollicular epidermis, whereas contribution to hair lineages gradually diminished with age. Adult Lgr6+ cells executed long-term wound repair, including the formation of new hair follicles. We conclude that Lgr6 marks the most primitive epidermal stem cell.
1 Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.
2 Karolinska Institutet, Center for Biosciences and Department of Biosciences and Nutrition, Novum, SE-141 57 Huddinge, Sweden.* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: h.clevers@hubrecht.eu
Interesting points in the paper
- Both integrations create null alleles. Homozygous mice of both strains were healthy and fertile.
- Lgr6 is thus one of the earliest placode markers, resembling Sonic Hedgehog and Sox9.
- Lgr6 marked the central isthmus directly above the bulge, whereas Lgr4 expression was present in both the Lgr5+ and the Lgr6+ domains (Fig. 2B).
- The only gene in the Lgr6 profile implicated in stem cell biology and HF development was Tnfrsf19/Troy (28, 29).
- Multipotency of donor stem cells was confirmed by activating the R26R-LacZ locus in vivo 4 days before isolation. A small subset of Lgr6+ stem cells became LacZ-positive and contributed, once transplanted, to all skin lineages (Fig. 3F and fig. S6F).
- Our study identifies Lgr6 as a marker for a distinct population of stem cells giving rise to all lineages of the skin. Unlike the Lgr5 gene, we found no evidence that Lgr6 is controlled by Wnt signaling. ... A picture thus emerges in which a Wnt-independent Lgr6 stem cell pool can renew sebaceous cells and seed the epidermis throughout life, whereas a Wnt-dependent Lgr5 stem cell pool derives from the Lgr6 pool early in life but then becomes relatively independent.
F1000 review is http://f1000biology.com/article/id/2576957/evaluation
Yukiko Yamashita
University of Michigan, Ann Arbor, United States of America
Developmental Biology
Lgr proteins (leucine-rich repeat-containing G protein-coupled receptors) have become the gold mine in the stem cell field. This paper identifies another Lgr, Lgr6, as a marker of most primitive stem cells in the hair follicle.
The authors demonstrate that Lgr6+ stem cells are distinct from Lgr5+ stem cells, more primitive than Lgr5+ cells, and Wnt-independent. Now, a pressing question is if there might be differential ligands for these receptors (if indeed they require ligands).
Ian Macara
University of Virginia, United States of America
Developmental Biology
This important paper identifies Lgr6 as a marker for a previously unknown population of stem cells that can generate all lineages of the skin, including hair follicles, sebaceous glands and interfollicular epidermis.
Lgr6 is a member of a family of orphan G-protein-coupled receptors that possess a large leucine-rich repeat-containing extracellular domain. Another member of the family, Lgr5, was shown previously by Clevers and coworkers to mark intestinal and hair follicle stem cells {1}. Now another family member, Lgr6, is found to be a marker for a primitive skin stem cell. There are two striking features of this work. First, it provides further evidence in support of the idea that tissues contain a hierarchy of stem cells, some of which might be actively cycling while others are normally dormant, and some of which can generate a broader array of cell fates than others. Second, the identification of Lgr6 as a stem cell marker suggests that this family of orphan receptors might all play functional roles in stem cell self-renewal or specification. Another member of the family, Lgr4, does not appear to mark a skin stem cell population and is broadly expressed, but it is essential for renal development and male reproductive tract development. It is conceivable, therefore, that Lgr4 might be associated with stem cells in these organs. The identification of bona fide stem cell surface markers is an important breakthrough that will enable their purification to homogeneity and subsequent analysis.
References: {1} Barker et al. Cold Spring Harb Symp Quant Biol 2008, 73:351-6 [PMID:19478326].