Gene name - fork head
Cytological map position - 98D1-E1
Function - transcription factor
Symbol - fkh
Genetic map position -
Classification - forkhead domain
Cellular location - nuclear
|Recent literature||Bolukbasi, E., Khericha, M., Regan, J. C., Ivanov, D. K., Adcott, J., Dyson, M. C., Nespital, T., Thornton, J. M., Alic, N. and Partridge, L. (2017). Intestinal Fork head regulates nutrient absorption and promotes longevity. Cell Rep 21(3): 641-653. PubMed ID: 29045833
Reduced activity of nutrient-sensing signaling networks can extend organismal lifespan, yet the underlying biology remains unclear. This study shows that the anti-aging effects of rapamycin and reduced intestinal insulin/insulin growth factor (IGF) signaling (IIS) require the Drosophila FoxA transcription factor homolog Fork Head (FKH). Intestinal FKH induction extends lifespan, highlighting a role for the gut. FKH binds to and is phosphorylated by AKT and Target of Rapamycin. Gut-specific FKH upregulation improves gut barrier function in aged flies. Additionally, it increases the expression of nutrient transporters, as does lowered IIS. Evolutionary conservation of this effect of lowered IIS is suggested by the upregulation of related nutrient transporters in insulin receptor substrate 1 knockout mouse intestine. These studies highlights a critical role played by FKH in the gut in mediating anti-aging effects of reduced IIS. Malnutrition caused by poor intestinal absorption is a major problem in the elderly, and a better understanding of the mechanisms involved will have important therapeutic implications for human aging.
|Lan, Q., Cao, M., Kollipara, R. K., Rosa, J. B., Kittler, R. and Jiang, H. (2017). FoxA transcription factor Fork head maintains the intestinal stem/progenitor cell identities in Drosophila. Dev Biol 433(2):324-343. PubMed ID: 29108672
Understanding how somatic stem cells respond to tissue needs is important, since aberrant somatic stem cell behaviors may lead to tissue degeneration or tumorigenesis. From an in vivo RNAi screen targeting transcription factors that regulate intestinal regeneration, this study uncovered a requirement for the Drosophila FoxA transcription factor Fork head (Fkh) in the maintenance of intestinal stem/progenitor cell identities. FoxA/Fkh maintains the expressions of stem/progenitor cell markers and is required for stem cell proliferation during intestinal homeostasis and regeneration. Furthermore, FoxA/Fkh prevents the intestinal stem/progenitor cells from precocious differentiation into the Enterocyte lineage, likely in cooperation with the transcription factor bHLH/Daughterless (Da). In addition, loss of FoxA/Fkh suppresses the intestinal tumorigenesis caused by Notch pathway inactivation. To reveal the gene program underlying stem/progenitor cell identities, the genome-wide chromatin binding sites of transcription factors Fkh and Da were profiled, and interestingly, around half of Fkh binding regions are shared by Da, further suggesting their collaborative roles. Finally, the genes were identified associated with their shared binding regions. This comprehensive gene list may contain stem/progenitor maintenance factors functioning downstream of Fkh and Da, and would be helpful for future gene discoveries in the Drosophila intestinal stem cell lineage.
The process of gastrulation in the fly is a little confusing for those familiar with gastrulation in vertebrates, such as the frog. In the frog, the egg is divided into animal and vegetal poles. The animal pole gives rise to ectoderm, the so-called active developmental tissue, progenitor of the future head, backbone and somatic structures. The vegetal pole gives rise to endoderm, tissue that forms the internal organs such as the digestive system. Seeing the ventral invagination in the fly, one might assume the process is homologous to what occurs in the frog, and that this developmentally driven ventral inturning of cells is also the origin of endoderm in the fly, as it is in the frog. This is not the case however.
The fly's development in this instance seems to be more complex than that of the frog and definitely more alien, when viewed from a vertebrate perspective. The fly has not one but three loci for invagination [Images]: the ventral locus mentioned above, plus one at either end (anterior and posterior) of the fertilized egg. Ventral invagination in the fly is driven by the genes twist and snail, and forms the mesoderm. fork head drives the anterior and posterior loci of invagination. From these are formed the anterior midgut and posterior midgut primordia, which give rise to the endoderm. Therefore, cells that will eventually become the fly's digestive system come from the "head" and "tail" ends of the egg, not the ventral or "stomach" side, as is intuitively suggested by vertebrate development. The vegetal pole in vertebrate eggs may be considered analogous to the amnioserosa in the fly, a tissue that contracts and disappears during germ band extention.
fork head expression marks both the anterior and posterior gut primordia. Gut primordia are the anlagen of the endodermal anterior midgut (anterior pole) and the endodermal posterior midgut (posterior pole). A major part of the invaginating anterior anlage is ectoderm. Anterior derivatives include the foregut (pharynx and esophagus, and the hindgut (proctodeum). The posterior domain abuts the seventh Fushi tarazu stripe and therefore is behind the 15th parasegment (the last FTZ stripe is two parasegments wide).
Posterior fork head expression follows the amnioproctodeal invagination during gastrulation and anterior expression spreads into the invaginating primordia of the anterior midgut. This expression profile suggests that fork head defines both anterior and posterior gut primordia and regulates the invagination process.
An analysis of mutant phenotypes helps clarify fork head's function. In both anterior and posterior domains, fork head mutations cause homeotic transformation of portions of the gut: foregut and hindgut are replaced by ectopic head structures in fkh mutants (Weigel, 1989).
Anterior and posterior fork head expression and function are independently regulated. In one class of regulatory mutants, there is specific failure to form a stomodeal invagination (Weigel, 1990a).
From the vertebrate biologist's viewpoint, the mystery of Drosophila Fork head is its lack of mesodermal expression. Fork head's closest vertebrate homologs, HNF-3alpha, HNF-3beta, HNF-3gamma, XFKH1/XFD1, and XFD1/pintallavis are each expressed in mesoderm, and are involved in fate determination of endoderm, neural ectoderm, notochord and other mesodermal tissues.
The secretory tubes of the Drosophila salivary glands are formed by the regulated, sequential internalization of the primordia. Secretory cell invagination occurs by a change in cell shape, which includes basal nuclear migration and apical membrane constriction. In embryos mutant for fork head, the secretory primordia are not internalized and secretory tubes do not form. Secretory cells of fkh mutant embryos undergo extensive apoptotic cell death following the elevated expression of the apoptotic activator genes reaper and head involution defective. The secretory cell death can be rescued in the fkh mutants and the rescued cells still do not invaginate. The rescued fkh secretory cells undergo basal nuclear migration in the same spatial and temporal pattern as in wild-type secretory cells, but do not constrict their apical surface membranes. These findings suggest at least two roles for fkh in the formation of the embryonic salivary glands: an early role in promoting survival of the secretory cells, and a later role in secretory cell invagination, specifically in the constriction of the apical surface membrane (Myat, 2000).
FKH mRNA was first detected during embryonic stage 9 in the ventral-posterior cells of the secretory placode. FKH mRNA is detected at approximately equivalent levels in all secretory cells from early embryonic stage 10 and throughout embryogenesis. Fkh is expressed in the salivary glands of late third instar larvae where it activates expression of the Salivary gland secretion protein 3 (Sgs3) and Salivary gland secretion protein 4 (Sgs4) genes. This late expression suggests that fkh is expressed in the salivary gland throughout the larval stages until the onset of metamorphosis (Myat, 2000).
The apoptotic cell death observed in the early secretory primordia of fkh mutants indicates that fkh is required for secretory cell survival. Thus, secretory cells may fail to invaginate in fkh mutants simply because the cells are dead or dying. Indeed, the ectopic expression of rpr and hid, but not grim, is effective in inducing early secretory cell death, which if extensive enough, prevents internalization. Alternatively, fkh may have two separate roles in the salivary gland, one to promote cell survival and another to control invagination of the primordia. To distinguish between these possibilities, the apoptotic secretory cell death was rescued in fkh mutants by generating embryos that were mutant for fkh and also carried Df(3L)H99, a small deficiency that deletes rpr, hid and grim (fkh H99). Normal salivary glands are formed in embryos homozygous for Df(3L)H99 (H99). In the fkh H99 embryos, dCREB-A staining is detected in the entire secretory placode at early stages This staining completely disappears by embryonic stage 13, suggesting that either fkh is required to maintain dCREB-A expression or that the fkh H99 secretory cells are still dying. To address this issue, the expression of another secretory marker protein, PS, whose expression is thought to be fkh independent, was analyzed. In wild-type embryos, PS is expressed at high levels in the salivary glands throughout embryogenesis. In fkh mutant embryos, PS is initially expressed in the entire secretory placode, and at reduced levels in the surviving ring of secretory cells. Importantly, PS is expressed to very high levels in all secretory cells throughout embryogenesis in the fkh H99 embryos. Nonetheless, the PS-expressing cells in the fkh H99 embryos are not internalized and remain at their site of origin on the ventral surface. Therefore, in addition to its early role in promoting secretory cell survival, Fkh is also required for the invagination of the secretory cells (Myat, 2000).
Histological sections and transmission electron microscope analyses of fkh H99 embryos confirm the failure of the secretory cells to be internalized and reveal additional changes in the salivary glands. Cells of the fkh H99 placode are columnar like the wild-type cells, except for cells in the ventral-posterior portion of the placode, which are round and stacked on one another. Interestingly, although coordinate nuclear migration occurs in the secretory cells of all fkh H99 embryos in approximately the same temporal and spatial pattern as in wild type, the apical surface membranes fail to constrict even at very late stages. Consequently, the invaginating pits of fkh H99 salivary glands are wide and shallow compared to those of wild-type embryos. The absence of apical membrane constriction was confirmed by analyzing transmission electron micrographs of invaginating wild-type and fkh secretory cells. Prior to invagination, wild-type secretory cells have broad and flat apices. Wild-type secretory cells at the center of the invaginating pit have constricted apices, and show numerous membrane protrusions at the apical surface. In contrast, secretory cells at the lateral edges of the invaginating pit, have flat and broad apices with few membrane protrusions. In late fkh H99 embryos, the apices of the secretory cells are unconstricted and appear flat and broad, similar to the apices of secretory cells in early wild-type embryos. Fewer apical membrane protrusions are found at the surface of fkh H99 secretory cells, as compared to wild type. Altogether, these findings suggested that fkh is required for secretory cells both to survive and to invaginate. Moreover, the absence of apical membrane constriction may be the underlying defect in the failure of fkh mutant salivary glands to internalize (Myat, 2000).
Introns - none
Bases in 3' UTR - 1762
The protein structural domain, termed the Forkhead domain, of which Fork head protein is the archetype, consists of 114 amino acids, having a globular structure with 37% alpha-helix content. Specific interaction with DNA is mediated by two contact regions, separated by one turn of DNA (Kaufman, 1994).
date revised: 30 Dec 96
Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.
The Interactive Fly resides on the
Society for Developmental Biology's Web server.