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Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair.

Larin M, Gallo D, Tamblyn L, Yang J, Liao H, Sabat N, Brown GW, McPherson JP - Nucleic Acids Res. (2014)

Bottom Line: Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair.This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity.Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.

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Increased prevalence of congenital defects in FkoMko mice. (a) Representative image illustrating characteristic craniofacial features of FkoMko mice compared to the normal appearance of FkoMhet controls. (b, c) Representative X-ray of skulls showing deviated rostrum, micrognathia and abnormal dentition in FkoMko mice (c) compared to that of FhetMko control (b). (d, e) Representative X-rays of skulls showing abnormal skull shape and pronounced microcephaly in FkoMko mice (e) compared to that of FhetMko controls (d). (f-i). Representative images of diverse ocular defects observed. (f) Normal eye. (g) Corneal opacity/cataract. (h) Microphthalmia. (i) Anophthalmia. (j) Table indicating frequency of observed congenital abnormalities, P-values calculated by Fisher's exact test with significant differences in bold font.
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Figure 2: Increased prevalence of congenital defects in FkoMko mice. (a) Representative image illustrating characteristic craniofacial features of FkoMko mice compared to the normal appearance of FkoMhet controls. (b, c) Representative X-ray of skulls showing deviated rostrum, micrognathia and abnormal dentition in FkoMko mice (c) compared to that of FhetMko control (b). (d, e) Representative X-rays of skulls showing abnormal skull shape and pronounced microcephaly in FkoMko mice (e) compared to that of FhetMko controls (d). (f-i). Representative images of diverse ocular defects observed. (f) Normal eye. (g) Corneal opacity/cataract. (h) Microphthalmia. (i) Anophthalmia. (j) Table indicating frequency of observed congenital abnormalities, P-values calculated by Fisher's exact test with significant differences in bold font.

Mentions: In addition to the overall decrease in mass and size, FkoMko mice exhibited dysmorphic facial features along with increased susceptibility to other congenital abnormalities (Figure 2). Typically, FkoMko mice exhibited micrognathia and more pronounced foreheads than siblings (Figure 2A). In 11 of 26 FkoMko mice examined (42.3%), X-ray analysis showed overt abnormalities in the overall shape and symmetry of the skull compared to three of 27 FkoMhet mice (P = 0.0012; Figure 2B–E). All FkoMko mice exhibited eye abnormalities (retinal opacity, microphthalmia and anophthalmia; Figure 2F–I) compared to FkoMhet mice (77% incidence, P = 0.02), in particular the incidence of bilateral versus unilateral microphthalmia (P = 0.004) and bilateral versus unilateral anophthalmia (P = 0.046). Furthermore, a low percentage of FkoMko mice showed additional abnormalities such as hypopigmentation of coat fur, and trended toward susceptibility to hydrocephalus (14.8% incidence) compared to FkoMhet mice (3.7% incidence; Figure 2J). No differences in hematological parameters were observed among the genotypes examined (Supplementary Figure S1). Overall, FkoMko mice exhibited increased severity and frequency of phenotypes observed in Fko mice as well as novel traits not observed in either Fko or Mko mice.


Fanconi anemia signaling and Mus81 cooperate to safeguard development and crosslink repair.

Larin M, Gallo D, Tamblyn L, Yang J, Liao H, Sabat N, Brown GW, McPherson JP - Nucleic Acids Res. (2014)

Increased prevalence of congenital defects in FkoMko mice. (a) Representative image illustrating characteristic craniofacial features of FkoMko mice compared to the normal appearance of FkoMhet controls. (b, c) Representative X-ray of skulls showing deviated rostrum, micrognathia and abnormal dentition in FkoMko mice (c) compared to that of FhetMko control (b). (d, e) Representative X-rays of skulls showing abnormal skull shape and pronounced microcephaly in FkoMko mice (e) compared to that of FhetMko controls (d). (f-i). Representative images of diverse ocular defects observed. (f) Normal eye. (g) Corneal opacity/cataract. (h) Microphthalmia. (i) Anophthalmia. (j) Table indicating frequency of observed congenital abnormalities, P-values calculated by Fisher's exact test with significant differences in bold font.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150781&req=5

Figure 2: Increased prevalence of congenital defects in FkoMko mice. (a) Representative image illustrating characteristic craniofacial features of FkoMko mice compared to the normal appearance of FkoMhet controls. (b, c) Representative X-ray of skulls showing deviated rostrum, micrognathia and abnormal dentition in FkoMko mice (c) compared to that of FhetMko control (b). (d, e) Representative X-rays of skulls showing abnormal skull shape and pronounced microcephaly in FkoMko mice (e) compared to that of FhetMko controls (d). (f-i). Representative images of diverse ocular defects observed. (f) Normal eye. (g) Corneal opacity/cataract. (h) Microphthalmia. (i) Anophthalmia. (j) Table indicating frequency of observed congenital abnormalities, P-values calculated by Fisher's exact test with significant differences in bold font.
Mentions: In addition to the overall decrease in mass and size, FkoMko mice exhibited dysmorphic facial features along with increased susceptibility to other congenital abnormalities (Figure 2). Typically, FkoMko mice exhibited micrognathia and more pronounced foreheads than siblings (Figure 2A). In 11 of 26 FkoMko mice examined (42.3%), X-ray analysis showed overt abnormalities in the overall shape and symmetry of the skull compared to three of 27 FkoMhet mice (P = 0.0012; Figure 2B–E). All FkoMko mice exhibited eye abnormalities (retinal opacity, microphthalmia and anophthalmia; Figure 2F–I) compared to FkoMhet mice (77% incidence, P = 0.02), in particular the incidence of bilateral versus unilateral microphthalmia (P = 0.004) and bilateral versus unilateral anophthalmia (P = 0.046). Furthermore, a low percentage of FkoMko mice showed additional abnormalities such as hypopigmentation of coat fur, and trended toward susceptibility to hydrocephalus (14.8% incidence) compared to FkoMhet mice (3.7% incidence; Figure 2J). No differences in hematological parameters were observed among the genotypes examined (Supplementary Figure S1). Overall, FkoMko mice exhibited increased severity and frequency of phenotypes observed in Fko mice as well as novel traits not observed in either Fko or Mko mice.

Bottom Line: Individuals with Fanconi anemia (FA) are susceptible to bone marrow failure, congenital abnormalities, cancer predisposition and exhibit defective DNA crosslink repair.This cooperativity of FancC and Mus81 in developmental outcome was also mirrored in response to crosslink damage and chromosomal integrity.Thus, our findings reveal that both pathways safeguard against DNA damage from exceeding a critical threshold that triggers proliferation arrest and apoptosis, leading to compromised in utero development.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, M5S 1A8, Canada.

Show MeSH
Related in: MedlinePlus