Animal models of ventral body wall closure defects: A personal perspective on gastroschisis

Williams, Trevor

doi:10.1002/ajmg.c.30179

Cited by 20 publications

(20 citation statements)

References 24 publications

(32 reference statements)

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“…Ventral body wall closure abnormalities, such as omphalocele, are common human birth defects, but their molecular and cellular bases are poorly understood [35]. The mouse provides a model system to study the genetic defects and environmental insults that can lead to ventral body wall closure abnormalities [20].…”

Section: Discussionmentioning

confidence: 99%

The physiological roles of vesicular GABA transporter during embryonic development: a study using knockout mice

et al. 2010

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BackgroundThe vesicular GABA transporter (VGAT) loads GABA and glycine from the neuronal cytoplasm into synaptic vesicles. To address functional importance of VGAT during embryonic development, we generated global VGAT knockout mice and analyzed them.ResultsVGAT knockouts at embryonic day (E) 18.5 exhibited substantial increases in overall GABA and glycine, but not glutamate, contents in the forebrain. Electrophysiological recordings from E17.5-18.5 spinal cord motoneurons demonstrated that VGAT knockouts presented no spontaneous inhibitory postsynaptic currents mediated by GABA and glycine. Histological examination of E18.5 knockout fetuses revealed reductions in the trapezius muscle, hepatic congestion and little alveolar spaces in the lung, indicating that the development of skeletal muscle, liver and lung in these mice was severely affected.ConclusionVGAT is fundamental for the GABA- and/or glycine-mediated transmission that supports embryonic development. VGAT knockout mice will be useful for further investigating the roles of VGAT in normal physiology and pathophysiologic processes.

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Section: Discussionmentioning

confidence: 99%

The physiological roles of vesicular GABA transporter during embryonic development: a study using knockout mice

et al. 2010

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“…During normal development, a mature body wall covers the ventral surface surrounding the ring and the cord. With omphalocele, the mature body wall shows incomplete closure and it is localized to the periphery of the enlarged umbilical ring [82].…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of Hedgehog Signaling in Ventral Body Wall Development and the Onset of Omphalocele Formation

et al. 2011

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BackgroundAn omphalocele is one of the major ventral body wall malformations and is characterized by abnormally herniated viscera from the body trunk. It has been frequently found to be associated with other structural malformations, such as genitourinary malformations and digit abnormalities. In spite of its clinical importance, the etiology of omphalocele formation is still controversial. Hedgehog (Hh) signaling is one of the essential growth factor signaling pathways involved in the formation of the limbs and urogenital system. However, the relationship between Hh signaling and ventral body wall formation remains unclear.Methodology/Principal FindingsTo gain insight into the roles of Hh signaling in ventral body wall formation and its malformation, we analyzed phenotypes of mouse mutants of Sonic hedgehog (Shh), GLI-Kruppel family member 3 (Gli3) and Aristaless-like homeobox 4 (Alx4). Introduction of additional Alx4Lst mutations into the Gli3Xt/Xt background resulted in various degrees of severe omphalocele and pubic diastasis. In addition, loss of a single Shh allele restored the omphalocele and pubic symphysis of Gli3Xt/+; Alx4Lst/Lst embryos. We also observed ectopic Hh activity in the ventral body wall region of Gli3Xt/Xt embryos. Moreover, tamoxifen-inducible gain-of-function experiments to induce ectopic Hh signaling revealed Hh signal dose-dependent formation of omphaloceles.Conclusions/SignificanceWe suggest that one of the possible causes of omphalocele and pubic diastasis is ectopically-induced Hh signaling. To our knowledge, this would be the first demonstration of the involvement of Hh signaling in ventral body wall malformation and the genetic rescue of omphalocele phenotypes.

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“…There are several examples of experimental models for gastroschisis, including genetic-and teratogen-induced cases, primarily in mice [Feldkamp et al, 2007;Williams, 2008]. However, most of these models focus on body folding as the potential mechanism for the defect and do not support a vascular hypothesis.…”

Section: Experimental Datamentioning

confidence: 99%

Examining the evidence for vascular pathogenesis of selected birth defects

Sadler

Rasmussen

2010

American J of Med Genetics Pt A

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Vascular mechanisms have been proposed to be involved in the pathogenesis of a number of defects, including transverse-limb defects, intestinal atresias, gastroschisis, hydranencephaly, porencephaly, oromandibular-limb hypogenesis sequence, and oculoauriculovertebral spectrum (OAVS). Here, we examine the available clinical, epidemiologic, and experimental evidence for four defects (transverse-limb defects, intestinal atresias, gastroschisis, and OAVS) for which vascular pathogenesis has been hypothesized. Based on our review, transverse-limb defects appear to sometimes be due to vascular events related to placental vascular abnormalities, hypoperfusion, abnormal development of blood vessels, intrauterine compression, hemoglobinopathies, or exposure to vasoactive agents, although epidemiological studies have not consistently demonstrated the latter association. However, transverse-limb defects can also be due to abnormal developmental events, such as aberrant molecular signaling in the apical ectodermal ridge. Some intestinal atresias may have a vascular origin, with the hypothesis supported by experiments in canines. However, evidence is accumulating that a more common mechanism might be related to improper molecular signaling related to gut specification early in development. In contrast, evidence to support vascular pathogenesis for gastroschisis and OAVS is less compelling. Instead, these defects probably arise from interference with basic developmental events [e.g., body wall closure (gastroschisis) and neural crest cell development (OAVS)]. These conclusions are important for counseling parents of children with these defects and for guiding the design of future epidemiological studies and experiments to further characterize the causes of these defects.

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Animal models of ventral body wall closure defects: A personal perspective on gastroschisis

Cited by 20 publications

References 24 publications

The physiological roles of vesicular GABA transporter during embryonic development: a study using knockout mice

The physiological roles of vesicular GABA transporter during embryonic development: a study using knockout mice

Genetic Analysis of Hedgehog Signaling in Ventral Body Wall Development and the Onset of Omphalocele Formation

Examining the evidence for vascular pathogenesis of selected birth defects

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