Retinoic acid‐induced inner ear teratogenesis caused by defective <i>Fgf3/Fgf10</i>‐dependent <i>Dlx5</i> signaling

Liu, Wei; Levi, Giovanni; Shanske, Alan; Frenz, Dorothy A.

doi:10.1002/bdrb.20154

Cited by 16 publications

(33 citation statements)

References 61 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…4 Los embriones humanos son más sensibles a la isotretinoína que los embriones de otras especies debido a la lenta eliminación del fármaco y a la isomerización continua del ácido retinoico. 5 La isotretinoína incrementa el riesgo de abortos espontáneos y mortinatos hasta un 40% en embarazos expuestos en el primer trimestre a este medicamento.…”

Section: Discussionunclassified

Embriopatía por isotretinoína con microtia-anotia y cardiopatía. Presentación de un caso

Pachajoa

Ordóñez

2012

Arch Argent Pediat

View full text Add to dashboard Cite

Presentación de casos clínicos RESUMENLa isotretinoína es un retinoide derivado de la vitamina A utilizado para el tratamiento del acné noduloquístico y refractario, pero ha sido catalogado como un medicamento teratogénico. Se ha comunicado un espectro de defectos congénitos que incluyen malformaciones craneofaciales, defectos cardíacos y defectos en el sistema nervioso con la exposición prenatal a este medicamento. Se presenta el caso de una recién nacida con antecedente de exposición prenatal a isotretinoína con defectos congénitos craneofaciales que incluyen parálisis facial, anotia derecha y microtia izquierda, y cardiopatía compleja. Palabras clave: isotretinoína, anormalidades congénitas, teratología. AbStRActIsotretinoin is a retinoid that derivates from vitamin A. It is indicated for recalcitrant nodular acne treatment, but it has been classified as teratogenic. A wide spectrum of birth defects including craniofacial, heart and nervous system malformations have been described associated to prenatal exposure to this drug. We report the case of a newborn with a history of prenatal exposure to isotretinoin with craniofacial defects, including facial paralysis, right anotia, left microtia and complex heart disease.

show abstract

Section: Discussionunclassified

Embriopatía por isotretinoína con microtia-anotia y cardiopatía. Presentación de un caso

Pachajoa

Ordóñez

2012

Arch Argent Pediat

View full text Add to dashboard Cite

show abstract

“…Interestingly, Fgf3 is downregulated in the otic vesicle by exposure to levels of retinoic acid (RA) that can cause inner ear malformations and capsule defects. Fgf3 is therefore a target of RA signaling that may also be involved in capsule chondrogenesis [31,32,33]. Expression of Fgf10 is similarly modified within the otic epithelium by aberrant RA exposure [31].…”

Section: Editorialmentioning

confidence: 99%

“…Fgf3 is therefore a target of RA signaling that may also be involved in capsule chondrogenesis [31,32,33]. Expression of Fgf10 is similarly modified within the otic epithelium by aberrant RA exposure [31]. When cultures of periotic mesenchyme containing otic epithelium are treated with high doses of RA, chondrogenesis is suppressed and levels of Fgf3 and Fgf10 are concomitantly reduced.…”

Section: Editorialmentioning

confidence: 99%

Inductive and Morphogenetic Responses of the Inner Ear to FGF Signaling

Frenz¹,

Maconochie²

2015

Anat Physiol

View full text Add to dashboard Cite

EditorialInner ear development entails a series of sequential inductive tissue interactions where one tissue signals to direct the development of adjacent tissue [s]. Inductive signals from mesodermal, endodermal, and neuroectodermal origin control multiple aspects of early inner ear formation. Signals arising from the endoderm and mesoderm that underlie the presumptive otic field in the cephalic surface ectoderm control induction of the otic placode from this region [1,2], whereas signals emanating from the neuroepithelium of the hindbrain direct invagination of the otic placode to form the otic vesicle. Subsequent morphogenesis of the otic vesicle into the elaborate three-dimensional inner ear occurs in response to yet another set of inductive interactions, this time between the epithelium of the otic vesicle, from which the cochlear and vestibular anlagen form, and the surrounding periotic mesenchyme. Thus all tissue layers in and around the otic region are involved in early inner ear development, and the likely molecular signals leading to these interactions are discussed below.Several members of the fibroblast growth factor (FGF) family from various tissue sources act together to direct different stages of otic vesicle formation [3]. The expression pattern of Fgf3 in the hindbrain adjacent to the developing otic placode [4] originally implicated Fgf3 as a likely candidate in otic induction. Overexpression of Fgf3 in the hindbrain of chicken embryos at a timepoint coincident with invagination of the otic placode resulted in ectopic formation of otic vesicles [2], whereas siRNA blockade of Fgf3 at this developmental stage led to partially invaginated placodes or failure to close the otic pits [2]. Thus in the chicken, Fgf3 is both sufficient and necessary for invagination of the otic placode to form the otic vesicle.However rather than there being any particular "master regulator" of early inner ear development, it has become clear that several FGFs are redundantly required to direct proper formation of the inner ear. Expression patterns of Fgf3 and other FGF ligands (or Fgf genes) partially overlap during inner ear formation, underscoring the importance of defining compensatory relationships between FGFs during this process. Besides FGF3, detection of Fgf10 expression in the hindbrain neuroepithelium coincides both temporally and spatially with development of the otic placode and vesicle [3], supporting its function as an inductive hindbrain-derived signal. Overexpression of Fgf10 in the anterior hindbrain of the mouse leads to the formation of ectopic vesicles that express markers confirming an early otic character, although the complete repertoire of otic marker expression was not obtained [3]. Overexpression of Fgf3 shows a more limited capacity to act as a hindbrain-derived inductive signal. Interestingly, mice homozygous for null mutation of either the Fgf3 [5] or Fgf10 [6] genes revealed unaltered induction of the otic vesicle, and development of seemingly normal albeit smaller otic vesicles. However, ...

show abstract

“…Of significant interest is the demonstration that RARa/RARg null embryos display severely hypoplastic otocysts where both otic chondrocyte differentiation and otic neural development are particularly affected (Romand et al, 2002), suggesting at least two independent cellular processes are controlled by RA signalling in the developing inner ear. Recently, we have shown by RT-PCR that Fgf3 expression in inner ear tissue appears to be downregulated and transcripts in the otic vesicle are not readily detectable following gavage administration of RA (Frenz et al, 1996(Frenz et al, , 2010Liu et al, 2008). Here we examine this relationship in detail and with enhanced sensitivity using Fgf3-reporter mice to investigate the spatiotemporal effects of RA on Fgf3 expression in the developing inner ear and in the whole embryo.…”

Section: Introductionmentioning

confidence: 97%

A novel method for retinoic acid administration reveals differential and dose‐dependent downregulation of Fgf3 in the developing inner ear and anterior CNS

Cadot

Frenz

Maconochie

2012

Developmental Dynamics

View full text Add to dashboard Cite

Endogenous retinoic acid plays critical roles in normal vertebrate development, but can be teratogenic in excess. In mice, additional retinoic acid is administered by oral gavage or intraperitoneal injection. Here we evaluate a novel non-invasive system for administering retinoic acid via chocolate/sugar pellets. We use this delivery system to examine the role of retinoic acid in regulating the expression of the fibroblast growth factor Fgf3, and find that the timing of retinoic acid treatment is critical for its effects on Fgf3 expression. Administration of increasing amounts of retinoic acid at 7.75 dpc leads to dose-dependent downregulation of Fgf3 in the otocyst and changes in spatial expression in the hindbrain. Detailed analysis of the developing inner ear also reveals a lateralisation of Fgf3 expression with increasing retinoic acid dose that is dependent on timing of administration. We discuss how these data impact on current models of retinoic acid patterning of the otocyst. Developmental Dynamics 241:741-758, 2012. V C 2012 Wiley Periodicals, Inc.Key words: fibroblast growth factor signaling; inner ear; hindbrain; retinoic acid; gavage Key findings:Administration of RA using chocolate/sugar pellets reproduces the range of phenotypes observed with gavage delivery. RA effects on anterior CNS formation and Fgf3 expression are dose-and time-dependent. Exogenous RA lateralizes and downregulates otic Fgf3 expression when administered at 7.75 dpc. In contrast, otic Fgf3 expression is only downregulated when RA is administered after hindbrain patterning.

show abstract

Retinoic acid‐induced inner ear teratogenesis caused by defective Fgf3/Fgf10‐dependent Dlx5 signaling

Abstract: Disruption in an Fgf3, -10/Dlx5 signaling cascade is operant in molecular mechanisms of inner ear teratogenesis by excess RA.

Cited by 16 publications

References 61 publications

Embriopatía por isotretinoína con microtia-anotia y cardiopatía. Presentación de un caso

Embriopatía por isotretinoína con microtia-anotia y cardiopatía. Presentación de un caso

Inductive and Morphogenetic Responses of the Inner Ear to FGF Signaling

A novel method for retinoic acid administration reveals differential and dose‐dependent downregulation of Fgf3 in the developing inner ear and anterior CNS

Contact Info

Product

Resources

About