scholarly journals Interrogation of a lacrimo-auriculo-dento-digital syndrome protein reveals novel modes of fibroblast growth factor 10 (FGF10) function

2016 ◽  
Vol 473 (24) ◽  
pp. 4593-4607 ◽  
Author(s):  
Marta Mikolajczak ◽  
Timothy Goodman ◽  
Mohammad K. Hajihosseini

Heterozygous mutations in the gene encoding fibroblast growth factor 10 (FGF10) or its cognate receptor, FGF-receptor 2 IIIb result in two human syndromes — LADD (lacrimo-auriculo-dento-digital) and ALSG (aplasia of lacrimal and salivary glands). To date, the partial loss-of-FGF10 function in these patients has been attributed solely to perturbed paracrine signalling functions between FGF10-producing mesenchymal cells and FGF10-responsive epithelial cells. However, the functioning of a LADD-causing G138E FGF10 mutation, which falls outside its receptor interaction interface, has remained enigmatic. In the present study, we interrogated this mutation in the context of FGF10's protein sequence and three-dimensional structure, and followed the subcellular fate of tagged proteins containing this or other combinatorial FGF10 mutations, in vitro. We report that FGF10 harbours two putative nuclear localization sequences (NLSs), termed NLS1 and NLS2, which individually or co-operatively promote nuclear translocation of FGF10. Furthermore, FGF10 localizes to a subset of dense fibrillar components of the nucleolus. G138E falls within NLS1 and abrogates FGF10's nuclear translocation whilst attenuating its progression along the secretory pathway. Our findings suggest that in addition to its paracrine roles, FGF10 may normally play intracrine role/s within FGF10-producing cells. Thus, G138E may disrupt both paracrine and intracrine function/s of FGF10 through attenuated secretion and nuclear translocation, respectively.

Development ◽  
1997 ◽  
Vol 124 (23) ◽  
pp. 4867-4878 ◽  
Author(s):  
S. Bellusci ◽  
J. Grindley ◽  
H. Emoto ◽  
N. Itoh ◽  
B.L. Hogan

During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48–60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.


2017 ◽  
Vol 102 ◽  
pp. 190-198 ◽  
Author(s):  
Mateus Nunes Diógenes ◽  
Ana Luiza Silva Guimarães ◽  
Ligiane Oliveira Leme ◽  
Machaim Franco Maurício ◽  
Margot Alves Nunes Dode

Reproduction ◽  
2010 ◽  
Vol 140 (6) ◽  
pp. 815-826 ◽  
Author(s):  
Kun Zhang ◽  
Peter J Hansen ◽  
Alan D Ealy

The ability of oocytes to resume meiosis, become fertilized, and generate viable pregnancies is controlled during folliculogenesis by several endocrine and paracrine factors. The aim of this work is to determine whether fibroblast growth factor 10 (FGF10) is an oocyte competent factor. Transcripts for each of the four FGF receptor types (FGFR) were present in cumulus and oocytes after their extraction from the follicles. FGFR1 transcripts predominated in cumulus cells whereas FGFR2 was most abundant in oocytes. Exposing the cumulus–oocyte complexes to FGF10 duringin vitromaturation did not affect cleavage rates, but increases (P<0.05) in the percentage of embryos at the 8–16-cell stage on day 3 and at the blastocyst stage on day 7, which were evident in FGF10-supplemented oocytes. The progression of oocytes through meiosis and cumulus expansion was increased (P<0.05) by FGF10. The importance of the endogenous sources of FGFs was examined by adding anti-FGF10 IgG during oocyte maturation. Blocking endogenous FGF10 activity decreased (P<0.05) the percentage of oocytes developing into blastocysts and limited (P<0.05) cumulus expansion. Expression profiles of putative cumulus and oocyte competency markers were examined for their involvement in FGF10-mediated responses. FGF10 influenced the expression ofCTSBandSPRY2in cumulus cells andBMP15in oocytes. In summary, this work provides new insight into the importance of FGFRs and locally derived FGF10 during oocyte maturation in cattle. Its subsequent impact onin vitroembryo development implicates it as a noteworthy oocyte competent factor.


1993 ◽  
Vol 265 (6) ◽  
pp. R1253-R1261 ◽  
Author(s):  
D. P. Basile ◽  
M. A. Holzwarth

We have investigated the role of basic fibroblast growth factor (bFGF) in the neurally mediated compensatory adrenal growth response. Unilateral adrenalectomy resulted in a 13, 6, and 22% increase in adrenal weight, protein, and DNA content, respectively, and 33-40% increases in the rate of cell proliferation measured by [3H]thymidine incorporation in vitro. Three forms of bFGF, approximately 18.6, 21, and 22.5 kDa, were identified in rat adrenals by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot. bFGF was localized immunocytochemically in cells of the glomerulosa and the medulla. bFGF stimulated a 68-80% increase in the rate of DNA synthesis in adrenal capsule-glomerulosa preparations in vitro. Suramin (0.1 mM), a growth factor antagonist, blocked bFGF receptor interaction in vitro and, at 200 mg/kg given 5-7 days before adrenal surgery, blocked compensatory growth. Conversely, at 2.0 mg/kg, suramin significantly enhanced the compensatory growth response, perhaps caused by suramin-induced bFGF receptor upregulation, since suramin pretreatment also enhanced DNA synthesis in response to exogenous bFGF in vitro. These results suggest that bFGF may mediate proliferation in the compensatory adrenal growth response.


2016 ◽  
Vol 34 (3) ◽  
pp. 383-390 ◽  
Author(s):  
Mateus Nunes Diógenes ◽  
Ana Luiza Silva Guimarães ◽  
Ligiane Oliveira Leme ◽  
Margot Alves Nunes Dode

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