Retinoic Acid-Induced Clubfoot-like Deformity

Delgado-Baeza, Emilio; Santos-Álvarez, Inmaculada; Martos-Rodríguez, A.

doi:10.1097/01202412-199901000-00003

Cited by 4 publications

(6 citation statements)

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“…An excess of retinoid compounds is associated with congenital malformations [20,21]. RA can induce CCF-like phenotypes in mice [12], and congenital malformations induced by RA are similar to those described in Sirt1 knockout mice [22,23]. However, the association of Sirt1 with CCF has not been reported.…”

Section: Resultsmentioning

confidence: 99%

“…Pitx1(+/−) mice and RA-treated pregnant rats can produce offspring with a CCF-like phenotype [11,12], but the abnormal expression of Pitx1 in idiopathic CCF has not been reported. Further research on the downstream effects of Pitx1 is required.…”

Section: Discussionmentioning

confidence: 99%

“…Sirt1 knockout mice exhibit similar malformations to those induced by RA activation [22]. Although RA can cause CCF-like phenotypes in mice [12], such phenotypes have not been reported in Sirt1 knockout mice, which may be related to mice with CCF induced by single-gene knockout of Pitx1. This situation is similar to early research, in which foot deformities occurred but were ignored by the researchers.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the E130K mutation of PITX1 (c.388G/A) suppressed wild-type Pitx1 activity in a dose-dependent manner in 9 affected individuals from a 5-generation family [7]. Additionally, research showed that a clubfoot-like phenotype was found in 20 of 225 Pitx1(+/−) mice [3,11,12]. These deformities include forefoot cavus in the frontal plane and hindfoot equinus in the sagittal plane (short Achilles tendon) and are associated with abnormalities of vascular, fibular bone volumes, and muscle volume in mice with the clubfoot-like phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Retinoic Acid Promotes Retinoic Acid Signaling by Suppression of Pitx1 In Tendon Cells: A Possible Mechanism of a Clubfoot-Like Phenotype Induced by Retinoic Acid

Zhao

Yang

2019

Med Sci Monit

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BackgroundThe pathogenesis of idiopathic congenital clubfoot (CCF) is unknown. Although some familial patients have Pitx1 mutations, and the Pitx1+/− genotype causes a clubfoot-like phenotype in mice, the mechanism of Pitx1-induced CCF is unknown.Material/MethodsWe used tibialis anterior tendon samples to detect the expression of Pitx1 in idiopathic and neurogenic clubfoot patients. After obtaining Sprague-Dawley (SD) rat Achilles tendon cells, the expression of Pitx1 was knocked down by SiRNA. After 48 h of culture, mass spectrometry was used to quantitatively analyze proteins. Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to assess the downstream pathway of PITX1. The relationship between Pitx1 and the promoter region of deacetylase 1 (Sirtuin-1 and Sirt1) was examined by luciferase and ChIP assays.ResultsWe found that Pitx1 expression in the tendon samples of idiopathic CCF patients was downregulated. Mass spectrometry analysis revealed that the inhibition of Pitx1 induced the downregulation of Sirt1 expression in tendon cells. Luciferase and ChIP assays confirmed that Pitx1 binds to the promoter region of SIRT1 and promotes Sirt1 gene transcription. Further results showed that, after the inhibition of Pitx1 in tendon cells, CRABP2 acetylation increased, the nuclear import of CRABP2 was enhanced, and the expression of RARβ2 increased. After the inhibition of Pitx1, RARβ2 expression was further increased by RA treatment in tendon cells. In the presence of retinoic acid, the expression of Pitx1 was inhibited in tendon cells.ConclusionsPitx1 binds to the promoter region of SIRT1 and promotes the transcription of SIRT1. Positive feedback occurs between RA signaling and Pitx1.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Retinoic Acid Promotes Retinoic Acid Signaling by Suppression of Pitx1 In Tendon Cells: A Possible Mechanism of a Clubfoot-Like Phenotype Induced by Retinoic Acid

Zhao

Yang

2019

Med Sci Monit

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“…Forty pregnant Wistar rats were obtained from the experimental animal center of our university. The ICTEV phenotype in rat embryos was induced by administration of 135 mg/kg all-trans-retinoic acid (ATRA) on gestation day 10 (GD10), as previously described [ 29 , 30 ]. All studies were performed with the approval of the experimental animal committee at our university (SCXK 2008-0005).…”

Section: Methodsmentioning

confidence: 99%

The expression of Gli3, regulated by HOXD13, may play a role in idiopathic congenital talipes equinovarus

Cao

Jin

Ren

et al. 2009

BMC Musculoskelet Disord

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BackgroundIdiopathic congenital talipes equinovarus (ICTEV) is a congenital limb deformity. Based on extended transmission disequilibrium testing, Gli-Kruppel family member 3 (Gli3) has been identified as a candidate gene for ICTEV. Here, we verify the role of Gli3 in ICTEV development.MethodsUsing the rat ICTEV model, we analyzed the differences in Gli3 expression levels between model rats and normal control rats. We used luciferase reporter gene assays and ChIP/EMSA assays to analyze the regulatory elements of Gli3.ResultsGli3 showed higher expression levels in ICTEV model rats compared to controls (P < 0.05). We identified repressor and activator regions in the rat Gli3 promoter. The Gli3 promoter also contains two putative Hoxd13 binding sites. Using EMSA, the Hoxd13 binding site 2 was found to directly interact with Hoxd13 in vitro. ChIP assays of the Hoxd13-Gli3 promoter complex from a developing limb confirmed that endogenous Hoxd13 interacts with this region in vivo.ConclusionOur findings suggest that HoxD13 directly interacts with the promoter of Gli3. The increase of Gli3 expression in ICTEV model animal might result from the low expression of HoxD13.

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Micro‐magnetic resonance imaging and embryological analysis of wild‐type and pma mutant mice with clubfoot

et al. 2009

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Gross similarities between the external appearance of the hind limbs of the peroneal muscle atrophy (pma) mouse mutant and congenital talipes equinovarus (CTEV), a human disorder historically referred to as ‘clubfoot’, suggested that this mutant could be a useful model. We used micro-magnetic resonance imaging to visualize the detailed anatomy of the hind limb defect in mutant pma mice and performed 3D comparisons between mutant and wild-type hind limbs. We found that the pma foot demonstrates supination (i.e. adduction and inversion of the mid foot and fore foot together with plantar flexion of the ankle and toes) and that the tibiale and distal tarsals display 3D abnormalities in positioning. The size and shape of the tibia, fibula, tarsal and metatarsal bones are similar to the wild-type. Hypoplasia of the muscles in the antero-lateral (peroneal) compartment was also demonstrated. The resemblance of these features to those seen in CTEV suggests that the pma mouse is a possibly useful model for the human condition. To understand how the observed deformities in the pma mouse hind foot arise during embryonic development, we followed the process of foot rotation in both wild-type and pma mutant mice. Rotation of the hind foot in mouse embryos of wild-type strains (CD-1 and C57/Black) occurs from embryonic day 14.5 onwards with rotation in C57/Black taking longer. In embryos from both strains, rotation of the right hind foot more commonly precedes rotation of the left. In pma mutants, the initiation of rotation is often delayed and rotation is slower and does not reach completion. If the usefulness of the pma mutant as a model is confirmed, then these findings on pma mouse embryos, when extrapolated to humans, would support a long-standing hypothesis that CTEV is due to the failure of completion of the normal process of rotation and angulation, historically known as the ‘arrested development hypothesis’.

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Retinoic Acid-Induced Clubfoot-like Deformity

Cited by 4 publications

References 0 publications

Retinoic Acid Promotes Retinoic Acid Signaling by Suppression of Pitx1 In Tendon Cells: A Possible Mechanism of a Clubfoot-Like Phenotype Induced by Retinoic Acid

Retinoic Acid Promotes Retinoic Acid Signaling by Suppression of Pitx1 In Tendon Cells: A Possible Mechanism of a Clubfoot-Like Phenotype Induced by Retinoic Acid

The expression of Gli3, regulated by HOXD13, may play a role in idiopathic congenital talipes equinovarus

Micro‐magnetic resonance imaging and embryological analysis of wild‐type and pma mutant mice with clubfoot

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