Fetal alcohol exposure impairs hedgehog cholesterol modification and signaling

Li, Yin‐Xiong; Yang, Haitao; Zdanowicz, Marzena; Sicklick, Jason K.; Qi, Yi; Camp, Terese; Diehl, Anna Mae

doi:10.1038/labinvest.3700516

Cited by 133 publications

(153 citation statements)

References 69 publications

Supporting

Mentioning

146

Contrasting

Order By: Relevance

“…The zebrafish has become a valid model for the study of CF development (14). Similar to previously reported zebrafish models of human genetic diseases, observed phenotypes are often more pronounced likely because of the rapid development and associated sensitivity to genetic perturbation (23,24).…”

Section: Discussionmentioning

confidence: 54%

Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet–Biedl syndrome

Tobin¹,

Franco

Eichers

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

175

171

View full text Add to dashboard Cite

Facial recognition is central to the diagnosis of many syndromes, and craniofacial patterns may reflect common etiologies. In the pleiotropic Bardet-Biedl syndrome (BBS), a primary ciliopathy with intraflagellar transport dysfunction, patients have a characteristic facial ''gestalt'' that dysmorphologists have found difficult to characterize. Here, we use dense surface modeling (DSM) to reveal that BBS patients and mouse mutants have mid-facial defects involving homologous neural crest-derived structures shared by zebrafish morphants. These defects of the craniofacial (CF) skeleton arise from aberrant cranial neural crest cell (NCC) migration. These effects are not confined to the craniofacial region, but vagal-derived NCCs fail to populate the enteric nervous system, culminating in disordered gut motility. Furthermore, morphants display hallmarks of disrupted Sonic Hedgehog (Shh) signaling from which NCCs take positional cues. We propose a model whereby Bbs proteins modulate NCC migration, contributing to craniofacial morphogenesis and development of the enteric nervous system. These migration defects also explain the association of Hirschsprung's disease (HD) with BBS. Moreover, this is a previously undescribed method of using characterization of facial dysmorphology as a basis for investigating the pathomechanism of CF development in dysmorphic syndromes.sonic hedgehog ͉ Wnt ͉ cilia ͉ cell migration R ecognition of the facial ''gestalt'' is central to diagnosis of many genetic disorders, but the great variability of features often hinders successful classification (1). Recently, noninvasive 3D surface imaging has characterized dysmorphology in syndromes (2, 3). None, however, has been used to either define subtle facial dysmorphism or aid investigation of mechanisms for craniofacial dysmorphology.Bardet-Biedl syndrome (BBS) causes retinal degeneration, postaxial polydactyly, obesity, renal dysfunction, and cognitive impairment. Twelve BBS genes (BBS1-BBS12) have been discovered, and pathogenesis lies in primary cilia dysfunction (4). BBS4, BBS6, and BBS8 (investigated in this study) are expressed in ciliated epithelia and localize to the centrosome and basal bodies of ciliated cells (5-7). Subtle craniofacial abnormalities in patients have been reported (8-10). Among the many additional features of BBS is Hirschsprung's disease (HD), a disorder of the enteric nervous system (ENS) (11).Streams of neural crest cells (NCCs) from the caudal brain form most of the craniofacial (CF) skeleton (see ref. 12 for review). Cranial NCCs (CNCC) follow defined paths to populate the frontonasal prominence and branchial arch mesenchyme. Here, they proliferate and differentiate into structures of the face and cranium. Sonic Hedgehog (Shh) expressed in the ventral brain and oral ectoderm is essential for the formation of most facial structures (12). Shh-deficient mice have severe loss of craniofacial bones, and, in humans, SHH mutations cause midline CF defects with holoprosencephaly (HPE) (12).The ENS regulates gastrointestina...

show abstract

Section: Discussionmentioning

confidence: 54%

Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet–Biedl syndrome

Tobin¹,

Franco

Eichers

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

175

171

View full text Add to dashboard Cite

show abstract

“…50 In addition to altering retinoic acid signaling, one alternative (or additional) mechanism by which ethanol attenuates Shh is the disruption of cholesterol modification of Shh needed for proper signaling, as has been found in zebrafish. 82 Further support for an involvement of Shh signaling in ethanol teratogenesis comes from genetic analyses (as we discuss in the next section).…”

Section: Zebrafish Models Of Fasdmentioning

confidence: 95%

“…78 Work in chicken, mouse, and zebrafish has shown that ethanol exposure reduces Shh signaling leading to increased CNCC death, as well as disrupted midline and eye development. 30,[79][80][81][82] These ethanol-induced phenotypes can be rescued by injection of shh mRNA. 50 In addition to altering retinoic acid signaling, one alternative (or additional) mechanism by which ethanol attenuates Shh is the disruption of cholesterol modification of Shh needed for proper signaling, as has been found in zebrafish.…”

Section: Zebrafish Models Of Fasdmentioning

confidence: 99%

Fishing for Fetal Alcohol Spectrum Disorders: Zebrafish as a Model for Ethanol Teratogenesis

2016

View full text Add to dashboard Cite

Fetal Alcohol Spectrum Disorders (FASD) describes a wide array of ethanol-induced developmental defects, including craniofacial dysmorphology and cognitive impairments. It affects *1 in 100 children born in the United States each year. Due to the pleiotropic effects of ethanol, animal models have proven critical in characterizing the mechanisms of ethanol teratogenesis. In this review, we focus on the utility of zebrafish in characterizing ethanolinduced developmental defects. A growing number of laboratories have focused on using zebrafish to examine ethanol-induced defects in craniofacial, cardiac, ocular, and neural development, as well as cognitive and behavioral impairments. Growing evidence supports that genetic predisposition plays a role in these ethanol-induced defects, yet little is understood about these gene-ethanol interactions. With a high degree of genetic amenability, zebrafish is at the forefront of identifying and characterizing the gene-ethanol interactions that underlie FASD.

show abstract

“…These models have several advantages over mammalian models with regard to fertilization, development and transperancy of the egg chorion. The effects of ethanol on zebrafish embryos have been studied by a number of investigators (Bilota et al, 2004;Carvan et al, 2004;Lockwood et al, 2004;Reimers et al, 2004;Arenzana et al, 2006;Li et al, 2007;Tanguay and Reimers, 2008), establishing that the fish can be used as a model organism to study FASD. Compared to zebrafish, medaka are less utilized in studying ethanol-induced toxicity.…”

Section: Introductionmentioning

confidence: 99%

Disruption of circulation by ethanol promotes fetal alcohol spectrum disorder (FASD) in medaka (Oryzias latipes) embryogenesis

Khan

Dasmahapatra

2008

Comparative Biochemistry and Physiology Part C: Toxicology &

View full text Add to dashboard Cite

Japanese medaka (Oryzias latipes) embryos exposed to ethanol have developed craniofacial, cardiovascular and skeletal defects which can be compared with the phenotypic features of fetal alcohol spectrum disorder (FASD) observed in human. The present experiment was designed to show that the disruption in circulation by ethanol during embryogenesis is a potential cause of FASD. Fertilized eggs were exposed to ethanol (0, 100 and/or 400 mM) for 24 or 48 h at various developmental stages (Iwamatsu stages 4-30) and were analyzed at 6 day post fertilization (dpf). It was observed that controls and the embryos exposed to 100 mM ethanol were in circulating state; however, a significant number of embryos of stages 4-24 exposed to 400 mM ethanol had disrupted circulation. Compared to controls, protein and RNA contents were significantly reduced in noncirculating embryos. Lipid peroxidation (LPO) analysis was made at 3, 6, 24, 48, 96 and 144 hour post fertilization (hpf). LPO was increased with the advancement of morphogenesis; however, ethanol or the circulation status had no effect. We further analyzed alcohol dehydrogenase (Adh 5 and adh8) and aldehyde dehydrogenase (Aldh9A and Aldh1A2) enzyme mRNAs in the embryos exposed to 400 mM ethanol for 24h. A developmental stage specific reduction in these enzyme mRNAs by ethanol was observed. We conclude that ethanol-induced disruption in circulation during embryogenesis is a potential cause of the development of FASD features in medaka.

show abstract

Fetal alcohol exposure impairs hedgehog cholesterol modification and signaling

Cited by 133 publications

References 69 publications

Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet–Biedl syndrome

Inhibition of neural crest migration underlies craniofacial dysmorphology and Hirschsprung's disease in Bardet–Biedl syndrome

Fishing for Fetal Alcohol Spectrum Disorders: Zebrafish as a Model for Ethanol Teratogenesis

Disruption of circulation by ethanol promotes fetal alcohol spectrum disorder (FASD) in medaka (Oryzias latipes) embryogenesis

Contact Info

Product

Resources

About