FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice

Marongiu, Mara; Marcia, Loredana; Pelosi, Emanuele; Lovicu, Mario; Deiana, Manila; Zhang, Yonqing; Puddu, Alessandro; Loi, Angela; Uda, Manuela; Forabosco, Antonino; Schlessinger, David; Crisponi, Laura

doi:10.1186/s12861-015-0072-y

Cited by 26 publications

(25 citation statements)

References 45 publications

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“…Most of the pelvis is formed and grows through a process of intramembranous ossification except the acetabulum, which also grows by endochondral ossification. Thus IGF-1 levels influence the size of the pelvic bones through its effects on ossification [38]. The strength of the association with PC1 was not markedly affected by exclusion of the related Greyhound/Labrador Retriever cross breeds because this association was driven by the dog breeds with lower representation (Table 6).…”

Section: Discussionmentioning

confidence: 99%

Genetic mapping of principal components of canine pelvic morphology

Fealey

Todhunter

et al. 2017

Canine Genet Epidemiol

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BackgroundConcentrated breeding effort to produce various body structures and behaviors of dogs to suit human demand has inadvertently produced unwanted traits and diseases that accompany the morphological and behavioral phenotypes. We explored the relationship between pelvic conformation and canine hip dysplasia (HD) because purebred dogs which are predisposed, or not, to HD share common morphologic features, respectively. Thirteen unique bilateral anatomical features of the pelvis were measured on 392 dogs of 51 breeds and 95 mixed breed dogs. Principal components (PCs) were derived to describe pelvic morphology. Dogs were genotyped at ~183,000 single nucleotide polymorphisms and their hip conformation was measured by the Norberg angle and angle of inclination between the femoral neck and diaphysis.ResultsNo associations reached genome wide significance for the Norberg angle when averaged over both hips. PC1 was negatively correlated with the Norberg angle (r = -0.31; P < 0.05) but not the angle of inclination (r = -0.08; P > 0.05). PC1, 2, 4, and 5 differed significantly between male and female dogs confirming pelvic sexual dimorphism. With sex as a covariate, the eigenvector contribution to PC1 reflected the overall size of the pelvis and was significantly associated with the IGF-1 locus, a known contributor to canine body size. PC3, which represented a tradeoff between ilial length and ischial length in which a longer ischium is associated with a shorter ilium, was significantly associated with a marker on canine chromosome 16:5181388 bp. The closest candidate gene is TPK1, a thiamine-dependent enzyme and part of the PKA complex. Associations with the remaining PCs did not reach genome wide significance.Conclusion IGF-1 was associated with the overall size of the pelvis and sex is related to pelvic size. Ilial/ischial proportion is genetically controlled and the closest candidate gene is thiamine-dependent and affects birth weight and development of the nervous system. Dogs with larger pelves tend to have smaller NAs consistent with increased tendency toward HD in large breed dogs. Based on the current study, pelvic shape alone was not strongly associated with canine hip dysplasia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40575-017-0043-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Genetic mapping of principal components of canine pelvic morphology

Fealey

Todhunter

et al. 2017

Canine Genet Epidemiol

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“…For the super shift experiment, EMSA reactions were pre-incubated for 20 min at room temperature with rabbit anti-HA (Santa Cruz sc805) or rabbit polyclonal anti-FOXL2, raised against residues FRPPPAHFQPGKGLF (Eurogentec s.a., Belgium) within the forkhead DNA binding domain and used after affinity purification; specificity was confirmed by western blotting. This antibody has been extensively used and validated in previous studies (Uda et al, 2004; Marongiu et al, 2010; Marongiu et al, 2015). For competition experiments, a 50- or 100-fold molar excess of unlabeled double-stranded WT oligonucleotide was included in the DNA binding reaction (Supplementary material Fig.…”

Section: Methodsmentioning

confidence: 99%

“…FOXL2 is also implicated as a master transcription factor in a range of developmental pathways that include growth and bone, cartilage and uterine maturation (Shi et al, 2014; Heude et al, 2015; Marongiu et al, 2015; Bellessort et al, 2015). In the pituitary gland, where it has been further analysed, it is expressed mainly in thyreotrope and gonadotrope cells (Ellsworth et al, 2006), and it has been reported that FOXL2 along with SMAD proteins in activin A induction, regulates Fshb expression in gonadotrope cells (Lamba et al, 2009; Tran et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Novel action of FOXL2 as mediator of Col1a2 gene autoregulation

Marongiu

Deiana

Marcia

et al. 2016

Developmental Biology

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FOXL2 belongs to the evolutionarily conserved forkhead box (FOX) superfamily and is a master transcription factor in a spectrum of developmental pathways, including ovarian and eyelid development and bone, cartilage and uterine maturation. To analyse its action, we searched for proteins that interact with FOXL2. We found that FOXL2 interacts with specific C-terminal propeptides of several fibrillary collagens. Because these propeptides can participate in feedback regulation of collagen biosynthesis, we inferred that FOXL2 could thereby affect the transcription of the cognate collagen genes. Focusing on COL1A2, we found that FOXL2 indeed affects collagen synthesis, by binding to a DNA response element located about 65Kb upstream of this gene. According to our hypothesis we found that in Foxl2−/− mouse ovaries, Col1a2 was elevated from birth to adulthood. The extracellular matrix (ECM) compartmentalizes the ovary during folliculogenesis, (with type I, type III and type IV collagens as primary components), and ECM composition changes during the reproductive lifespan. In Foxl2−/− mouse ovaries, in addition to up-regulation of Col1a2, Col3a1, Col4a1 and fibronectin were also upregulated, while laminin expression was reduced. Thus, by regulating levels of extracellular matrix components, FOXL2 may contribute to both ovarian histogenesis and the fibrosis attendant on depletion of the follicle reserve during reproductive aging and menopause.

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“…Foxl2 deletion in either CNCCs or CMCs prevents eyelid closure and induces subtle skeletal developmental defects [Heude et al, 2015]. In addition, FOXL2 is also involved in cartilage and skeletal formation, bone mineralization, and growth as demonstrated in a constitutive Foxl2 -deficient mice model [Shi et al, 2014;Marongiu et al, 2015].…”

Section: An Introduction To Foxl2: Early Findings the Mammalian Viewmentioning

confidence: 99%

Foxl2 and Its Relatives Are Evolutionary Conserved Players in Gonadal Sex Differentiation

Bertho

Pasquier

Pan

et al. 2016

Sex Dev

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Foxl2 is a member of the large family of Forkhead Box (Fox) domain transcription factors. It emerged during the last 15 years as a key player in ovarian differentiation and oogenesis in vertebrates and especially mammals. This review focuses on Foxl2 genes in light of recent findings on their evolution, expression, and implication in sex differentiation in animals in general. Homologs of Foxl2 and its paralog Foxl3 are found in all metazoans, but their gene evolution is complex, with multiple gains and losses following successive whole genome duplication events in vertebrates. This review aims to decipher the evolutionary forces that drove Foxl2/3 gene specialization through sub- and neo-functionalization during evolution. Expression data in metazoans suggests that Foxl2/3 progressively acquired a role in both somatic and germ cell gonad differentiation and that a certain degree of sub-functionalization occurred after its duplication in vertebrates. This generated a scenario where Foxl2 is predominantly expressed in ovarian somatic cells and Foxl3 in male germ cells. To support this hypothesis, we provide original results showing that in the pea aphid (insects) foxl2/3 is predominantly expressed in sexual females and showing that in bovine ovaries FOXL2 is specifically expressed in granulosa cells. Overall, current results suggest that Foxl2 and Foxl3 are evolutionarily conserved players involved in somatic and germinal differentiation of gonadal sex.

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FOXL2 modulates cartilage, skeletal development and IGF1-dependent growth in mice

Cited by 26 publications

References 45 publications

Genetic mapping of principal components of canine pelvic morphology

Genetic mapping of principal components of canine pelvic morphology

Novel action of FOXL2 as mediator of Col1a2 gene autoregulation

Foxl2 and Its Relatives Are Evolutionary Conserved Players in Gonadal Sex Differentiation

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