Retinoic Acid-Induced Clubfoot-like Deformity

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

doi:10.1097/00009957-199901000-00003

Cited by 10 publications

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“…The basis for this difference in the timing of rotation between right and left is not clear. One of the signals that is involved in setting up left/right asymmetry of the body in early vertebrate embryos is retinoic acid (Levin et al, 2006) and it is intriguing that, in rats, a single intragastric dose of retinoic acid (120 mg kg −1 body weight) on day 10 of pregnancy (Delgado-Baeza et al, 1999) invokes a ‘clubfoot’ phenotype. Analysis of heterozygous pma mice with unilateral ‘clubfoot’ also showed that the right foot was predominantly affected.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…These malformations have also been reproduced in our laboratory [Díez-Pardo et al, 1995]. A subsequent report describes the pathoanatomy of RA-induced clubfoot-like deformity; the results of that work show that there are rotational anomalies in the hindfoot and full hindlimb from the beginning of the fetal period, and that these anomalies increase during development [Delgado-Baeza et al, 1999]. However, the observation of hindlimb deformity described in those assays was made in rat fetuses, and the treatment with RA was carried out prior to the formation of the hindlimb bud.…”

Section: Introductionmentioning

confidence: 61%

“…It is known that retinoic acid (RA) is a potent teratogen responsible for a variety of abnormalities of organs and tissues in both humans [Lamer et al, 1985] and laboratory animals [Yasuda et al, 1986;Díez-Pardo et al, 1995;Delgado-Baeza et al, 1999]. Among the malformations produced by RA are hindlimb deformities, such as distortions in the shapes of long bones, fusion of bones, syndactylies, defects in ossification [Alles and Sulik, 1989] and clubfoot [Yasuda et al, 1986].…”

Section: Introductionmentioning

confidence: 99%

“…In the current work, we analyze the blastemic changes occurring in the embryo prior to the fetal period which may cause fetal hindlimb deformity using an experimental model [Delgado-Baeza et al, 1999]. After administration of all-trans-retinoic acid to pregnant rats on day 10 of pregnancy, the hindlimbs of 15-day embryos and the caudal somites of 11-day embryos were studied by mitosis count and using stereological, immunohistochemistry and AgNOR techniques.…”

Section: Introductionmentioning

confidence: 99%

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Embryonic Blastemic Changes in Retinoic Acid-Induced Hindlimb Deformity

Santos-Álvarez¹,

Martos-Rodríguez²,

Delgado-Baeza³

2003

Cells Tissues Organs

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In this study we analyzed, on an experimental model, blastemic changes occurring during the embryonic period that may later cause fetal hindlimb deformity. Experimental induction of clubfoot-like deformity in rat fetuses was performed by maternal administration of retinoic acid (RA) (120 mg/kg body weight) as a single intragastric dose on day 10 of pregnancy (previous phase of this assay). The caudal and hindlimb blastemic changes were studied by mitosis count and stereological, immunohistochemistry and AgNOR techniques in the hindlimbs of 15-day embryos and in the caudal somites of 11-day embryos. In 15-day embryos from the assay group, hypoplasia and misorientation of hindlimbs were present in 90% of the cases. The histological study showed a blastemal defect as follows: (a) reduction in mesenchymal cell activity (mitotic and AgNOR activities); (b) increase of volume of vascular lumen; (c) reduction in volume of nerve structures, and (d) reduction in the percentage of pre-rhabdomyoblastic cells. In 11-day embryos from the assay group, caudal somites showed disruption, including loss of usual morphology. Moreover, somitic AgNOR activity decreased compared to the control group. The greatest reduction in the number of black-dots per cell was in the myotome. These findings suggest that a certain pathology of the somites, very little studied to date, might be involved in clubfoot pathogenesis.

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“…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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Retinoic Acid-Induced Clubfoot-like Deformity

Cited by 10 publications

References 0 publications

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

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

Embryonic Blastemic Changes in Retinoic Acid-Induced Hindlimb Deformity

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

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