‘The VACTERL association: lessons from the Sonic hedgehog pathway’

Ml, Martínez-Frías; Bermejo, Eva; Frias, J L

doi:10.1034/j.1399-0004.2001.600515.x

Cited by 22 publications

(12 citation statements)

References 7 publications

(8 reference statements)

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“…Most strikingly, patients with PH syndrome can have laryngeal cleft and hypoplasia or absence of the epiglottis, similar to our findings for Sall3-deficient animals (4,19,38). Also, the VACTERL association that has been hypothesized to be a consequence of altered Shh signaling, includes tracheal-esophageal fistula, renal, limb, anal, and cardiac deficiencies (9,22,23,35,36,47). Our observations on the Sall3 phenotype strengthens the link between Sall and Shh signaling and raises the possibility that reduced Sall expression or signaling could contribute to the phenotypes observed in syndromes such as PH syndrome.…”

Section: Discussionsupporting

confidence: 74%

Loss of the Sall3 Gene Leads to Palate Deficiency, Abnormalities in Cranial Nerves, and Perinatal Lethality

Parrish

Ott

Lance‐Jones

et al. 2004

Molecular and Cellular Biology

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Members of the Spalt gene family encode putative transcription factors characterized by seven to nine C2H2 zinc finger motifs. Four genes have been identified in mice-Spalt1 to Spalt4 (Sall1 to Sall4). Spalt homologues are widely expressed in neural and mesodermal tissues during early embryogenesis. Sall3 is normally expressed in mice from embryonic day 7 (E7) in the neural ectoderm and primitive streak and subsequently in the brain, peripheral nerves, spinal cord, limb buds, palate, heart, and otic vesicles. We have generated a targeted disruption of Sall3 in mice. Homozygous mutant animals die on the first postnatal day and fail to feed. Examination of the oral structures of these animals revealed that abnormalities were present in the palate and epiglottis from E16.5. In E10.5 embryos, deficiencies in cranial nerves that normally innervate oral structures, particularly the glossopharyngeal nerve (IX), were observed. These studies indicate that Sall3 is required for the development of nerves that are derived from the hindbrain and for the formation of adjacent branchial arch derivatives.

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Section: Discussionsupporting

confidence: 74%

Loss of the Sall3 Gene Leads to Palate Deficiency, Abnormalities in Cranial Nerves, and Perinatal Lethality

Parrish

Ott

Lance‐Jones

et al. 2004

Molecular and Cellular Biology

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“…The easily recognizable VACTERL association is found in many clinical entities and syndromes of known causal factors, reflecting a heterogeneous etiology (Martinez-Frias et al, 1990; Kim et al, 2001; Martinez-Frias et al, 2001). …”

Section: Hypotheses Regarding Etiology Based On Clinical Observationsmentioning

confidence: 99%

A clinical and experimental overview of sirenomelia: insight into the mechanisms of congenital limb malformations

Garrido-Allepuz

Haro

González‐Lamuño

et al. 2011

Disease Models &Amp; Mechanisms

160

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Sirenomelia, also known as sirenomelia sequence, is a severe malformation of the lower body characterized by fusion of the legs and a variable combination of visceral abnormalities. The causes of this malformation remain unknown, although the discovery that it can have a genetic basis in mice represents an important step towards the understanding of its pathogenesis. Sirenomelia occurs in mice lacking Cyp26a1, an enzyme that degrades retinoic acid (RA), and in mice that develop with reduced bone morphogenetic protein (Bmp) signaling in the caudal embryonic region. The phenotypes of these mutant mice suggest that sirenomelia in humans is associated with an excess of RA signaling and a deficit in Bmp signaling in the caudal body. Clinical studies of sirenomelia have given rise to two main pathogenic hypotheses. The first hypothesis, based on the aberrant abdominal and umbilical vascular pattern of affected individuals, postulates a primary vascular defect that leaves the caudal part of the embryo hypoperfused. The second hypothesis, based on the overall malformation of the caudal body, postulates a primary defect in the generation of the mesoderm. This review gathers experimental and clinical information on sirenomelia together with the necessary background to understand how deviations from normal development of the caudal part of the embryo might lead to this multisystemic malformation.

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“…ARM phenotypes are also partly included in several diseases, such as Currarino syndromes, Townes Brocks Syndromes and VACTERL complex, and these patients display other anomalies including anal fistula, sacral malformations and renal malformations. 3, 4, 5, 6 …”

mentioning

confidence: 99%

Dysregulation of Wnt inhibitory factor 1 (Wif1) expression resulted in aberrant Wnt-β-catenin signaling and cell death of the cloaca endoderm, and anorectal malformations

Matsumaru

et al. 2014

Cell Death Differ

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In mammalian urorectal development, the urorectal septum (urs) descends from the ventral body wall to the cloaca membrane (cm) to partition the cloaca into urogenital sinus and rectum. Defective urs growth results in human congenital anorectal malformations (ARMs), and their pathogenic mechanisms are unclear. Recent studies only focused on the importance of urs mesenchyme proliferation, which is induced by endoderm-derived Sonic Hedgehog (Shh). Here, we showed that the programmed cell death of the apical urs and proximal cm endoderm is particularly crucial for the growth of urs during septation. The apoptotic endoderm was closely associated with the tempo-spatial expression of Wnt inhibitory factor 1 (Wif1), which is an inhibitor of Wnt-β-catenin signaling. In Wif1lacZ/lacZ mutant mice and cultured urorectum with exogenous Wif1, cloaca septation was defective with undescended urs and hypospadias-like phenotypes, and such septation defects were also observed in Shh−/− mutants and in endodermal β-catenin gain-of-function (GOF) mutants. In addition, Wif1 and Shh were expressed in a complementary manner in the cloaca endoderm, and Wif1 was ectopically expressed in the urs and cm associated with excessive endodermal apoptosis and septation defects in Shh−/− mutants. Furthermore, apoptotic cells were markedly reduced in the endodermal β-catenin GOF mutant embryos, which counteracted the inhibitory effects of Wif1. Taken altogether, these data suggest that regulated expression of Wif1 is critical for the growth of the urs during cloaca septation. Hence, Wif1 governs cell apoptosis of urs endoderm by repressing β-catenin signal, which may facilitate the protrusion of the underlying proliferating mesenchymal cells towards the cm for cloaca septation. Dysregulation of this endodermal Shh-Wif1-β-catenin signaling axis contributes to ARM pathogenesis.

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‘The VACTERL association: lessons from the Sonic hedgehog pathway’

Cited by 22 publications

References 7 publications

Loss of the Sall3 Gene Leads to Palate Deficiency, Abnormalities in Cranial Nerves, and Perinatal Lethality

Loss of the Sall3 Gene Leads to Palate Deficiency, Abnormalities in Cranial Nerves, and Perinatal Lethality

A clinical and experimental overview of sirenomelia: insight into the mechanisms of congenital limb malformations

Dysregulation of Wnt inhibitory factor 1 (Wif1) expression resulted in aberrant Wnt-β-catenin signaling and cell death of the cloaca endoderm, and anorectal malformations

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