Cyclopamine-Induced Holoprosencephaly and Associated Craniofacial Malformations in the Golden Hamster: Anatomic and Molecular Events

1998 ◽  
Vol 1 (1) ◽  
pp. 29-41 ◽  
Author(s):  
Susan Coventry ◽  
Raj P. Kapur ◽  
Joseph R. Siebert
Keyword(s):  
Neural Crest ◽  
Cleft Lip ◽  
Neural Plate ◽  
Early Event ◽  
Desert Plant ◽  
Craniofacial Malformations ◽  
Altered Expression ◽  
Facial Anomalies ◽  
Molecular Events ◽  
Cleft Lip Palate

Holoprosencephaly is a complex congenital malformation of the brain and is often associated with a spectrum of facial anomalies ranging from normocephaly or nondiagnostic changes to cleft lip/palate (premaxillary dysgenesis), cebocephaly ethmocephaly and cyclopia. The primary insult is thought to occur during gastrulation, when prechordal mesenchyme and overlying anterior neural plate undergo complex developmental interactions. Exposure to cyclopamine, a steroid isolated from the desert plant Veratrum californicum, causes holoprosencephaly in mammalian embryos. We have begun to study the pathogenesis of cyclopamine-induced holoprosencephaly and associated craniofacial anomalies in Syrian golden hamsters ( Mesocricetus auratus). Embryos were exposed to a single maternal dose of cyclopamine during gastrulation on embryonic day (E) 7.0. By E13.0, 62% of fetuses showed craniofacial malformations, including premaxillary dysgenesis, ocular hypotelorism, and cebocephaly. Facial anomalies were associated with absence of the premaxilla and abnormalities of the midline cranial base, particularly the ethmoid and sphenoid bones. Histological sections from cyclopamine-treated embryos at earlier stages showed marked deficiency of cranial mesenchyme derived from the rostral neural crest. Expression of two transcription factors, HNF-3β and Hox-b5, which have been implicated in specification of rostral and caudal neural crest cells, respectively, were examined immunohistochemically. Treatment with cyclopamine caused a transient loss of HNF-3β immunoreactivity in prechordal mesenchyme, but had no effect on Hox-b5 expression. The findings suggest that an early event in the pathogenesis of cyclopamine-induced holoprosencephaly may be altered expression of selected proteins in the prechordal mesenchyme and floor plate with secondary impaired development of the adjacent neural plate and cranial neural crest.

scholarly journals “mir152 hypomethylation, potentially triggered by embryonic hypoxia, as a common mechanism for non-syndromic cleft lip/palate”

2019 ◽  
Author(s):  
Lucas Alvizi ◽  
Luciano Abreu Brito ◽  
Bárbara Bischain ◽  
Camila Bassi Fernandes da Silva ◽  
Sofia Ligia Guimaraes Ramos ◽  
...  
Keyword(s):  
Cleft Lip ◽  
Differentially Methylated Region ◽  
Common Mechanism ◽  
Craniofacial Malformations ◽  
Predisposing Factor ◽  
Complex Disorder ◽  
Cleft Lip Palate ◽  
Functional Investigation

AbstractNon-syndromic cleft lip/palate (NSCLP), the most common human craniofacial malformations, is a complex disorder given its genetic heterogeneity and multifactorial component revealed by genetic, epidemiological and epigenetic findings. Association of epigenetic variations with NSCLP has been made, however still of little functional investigation. Here we combined a reanalysis of NSCLP methylome data with genetic analysis and used both in vitro and in vivo approaches to dissect the functional effects of epigenetic changes. We found a frequent differentially methylated region in mir152, hypomethylated in NSCLP cohorts (21-26%), leading to mir152 overexpression. In vivo analysis using zebrafish embryos revealed that mir152 upregulation leads to craniofacial impairment analogue to palatal defects. Also, we demonstrated that zebrafish embryonic hypoxia leads to mir152 upregulation combined with mir152 hypomethylation and also analogue palatal alterations. We therefore suggest mir152 hypomethylation, potentially induced by hypoxia in early development, as a novel and frequent predisposing factor to NSCLP.

The aetiology and pathogenesis of craniofacial deformity

Development ◽  
1988 ◽  
Vol 103 (Supplement) ◽  
pp. 207-212
Author(s):  
David Poswillo
Keyword(s):  
Neural Crest ◽  
Animal Studies ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Treacher Collins Syndrome ◽  
Apert Syndrome ◽  
Craniofacial Malformations ◽  
Craniofacial Microsomia ◽  
Animal System ◽  
Isolated Cleft Palate

Craniofacial malformations have been recorded since time immemorial. While observational studies have assisted in the recognition of syndromes, little light has been shed on the causal mechanisms which interfere with craniofacial development. Animal studies in which malformations occur spontaneously or have been induced by teratogenic agents have permitted step-by-step investigation of such common deformities as cleft lip and palate. The role of the ectomesenchymal cells of the neural crest and the possible phenomenon of disorganized spontaneous cell death are described in relation to lip clefts. The factors associated with isolated cleft palate, Pierre Robin syndrome and submucous clefts are described by reference to animal models. The haemorrhagic accident preceding the onset of craniofacial microsomia is discussed as is the distinctly different phenomenon of disturbance to the migration or differentiation of neural crest cells in the pathogenesis of Treacher Collins syndrome. The more severe anomalies of the calvarium such as plagiocephaly, Crouzon and Apert syndrome still defy explanation, in the absence of an appropriate animal system to study; some thoughts on the likely mechanism of abnormal sutural fusions are discussed.

scholarly journals Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development

2019 ◽  
Author(s):  
Marshall Lukacs ◽  
Tia Roberts ◽  
Praneet Chatuverdi ◽  
Rolf W. Stottmann
Keyword(s):  
Neural Crest ◽  
Neural Development ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Folate Receptor ◽  
Neural Crest Cell ◽  
Specific Expression ◽  
Hypomorphic Mutation ◽  
Pathogenic Variants ◽  
Cleft Lip Palate

AbstractThe glycosylphosphatidylinositol (GPI) anchor attaches nearly 150 proteins to the cell surface. Patients with pathogenic variants in GPI biosynthetic pathway genes display an array of phenotypes including seizures, developmental delay, dysmorphic facial features and cleft palate. There is virtually no mechanism to explain these phenotypes. we identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypomorphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2). Pgap2 is one of the final proteins in the GPI biosynthesis pathway and is required for anchor maturation. We found the Clpex mutation results in a global decrease in surface GPI expression. Surprisingly, Pgap2 showed tissue specific expression with enrichment in the affected tissues of the Clpex mutant. We found the phenotype in Clpex mutants is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium, as is observed in the GPI anchored Folate Receptor 1-/- mouse. We showed folinic acid supplementation in utero can rescue the cleft lip phenotype in Clpex. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency in the Wnt1-Cre lineage. These mutants developed median cleft lip and palate demonstrating a cell autonomous role for GPI biosynthesis in NCC development.

scholarly journals Ciliopathic micrognathia is caused by aberrant skeletal differentiation and remodeling

Development ◽  
2021 ◽  
Vol 148 (4) ◽  
pp. dev194175
Author(s):  
Christian Louis Bonatto Paese ◽  
Evan C. Brooks ◽  
Megan Aarnio-Peterson ◽  
Samantha A. Brugmann
Keyword(s):  
Neural Crest ◽  
Cleft Lip ◽  
Primary Cilia ◽  
Skeletal Development ◽  
Treatment Options ◽  
Cellular Processes ◽  
Cleft Lip Palate ◽  
Bona Fide ◽  
Bone Deposition ◽  
Osteoblast Maturation

ABSTRACTCiliopathies represent a growing class of diseases caused by defects in microtubule-based organelles called primary cilia. Approximately 30% of ciliopathies are characterized by craniofacial phenotypes such as craniosynostosis, cleft lip/palate and micrognathia. Patients with ciliopathic micrognathia experience a particular set of difficulties, including impaired feeding and breathing, and have extremely limited treatment options. To understand the cellular and molecular basis for ciliopathic micrognathia, we used the talpid2 (ta2), a bona fide avian model for the human ciliopathy oral-facial-digital syndrome subtype 14. Histological analyses revealed that the onset of ciliopathic micrognathia in ta2 embryos occurred at the earliest stages of mandibular development. Neural crest-derived skeletal progenitor cells were particularly sensitive to a ciliopathic insult, undergoing unchecked passage through the cell cycle and subsequent increased proliferation. Furthermore, whereas neural crest-derived skeletal differentiation was initiated, osteoblast maturation failed to progress to completion. Additional molecular analyses revealed that an imbalance in the ratio of bone deposition and resorption also contributed to ciliopathic micrognathia in ta2 embryos. Thus, our results suggest that ciliopathic micrognathia is a consequence of multiple aberrant cellular processes necessary for skeletal development, and provide potential avenues for future therapeutic treatments.

scholarly journals Ciliopathic micrognathia is caused by aberrant skeletal differentiation and remodeling

2020 ◽  
Author(s):  
Christian Louis Bonatto Paese ◽  
Evan C. Brooks ◽  
Megan Aarnio-Peterson ◽  
Samantha A. Brugmann
Keyword(s):  
Neural Crest ◽  
Cleft Lip ◽  
Primary Cilia ◽  
Skeletal Development ◽  
Treatment Options ◽  
Cellular Processes ◽  
Cleft Lip Palate ◽  
Bona Fide ◽  
Bone Deposition ◽  
Osteoblast Maturation

AbstractCiliopathies represent a growing class of diseases caused by defects in microtubule-based organelles called primary cilia. Approximately 30% of ciliopathies can be characterized by craniofacial phenotypes such as craniosynostosis, cleft lip/palate and micrognathia. Patients with ciliopathic micrognathia experience a particular set of difficulties including impaired feeding and breathing and have extremely limited treatment options. To understand the cellular and molecular basis for ciliopathic micrognathia, we utilized the talpid2 (ta2), a bona fide avian model for the human ciliopathy Oral-Facial-Digital syndrome subtype 14 (OFD14). Histological analyses revealed that the onset of ciliopathic micrognathia in ta2 embryos occurred at the earliest stages of mandibular development. Neural crest-derived skeletal progenitor cells were particularly sensitive to a ciliopathic insult, undergoing unchecked passage through the cell cycle and subsequent increased proliferation. Furthermore, whereas neural crest-derived skeletal differentiation was initiated, osteoblast maturation failed to progress to completion. Additional molecular analyses revealed that an imbalance in the ratio of bone deposition and resorption also contributed to ciliopathic micrognathia in ta2 embryos. Thus, our results suggest that ciliopathic micrognathia is a consequence of multiple, aberrant cellular processes necessary for skeletal development, and provide potential avenues for future therapeutic treatments.

scholarly journals Glycosylphosphatidylinositol biosynthesis and remodeling are required for neural tube closure, heart development, and cranial neural crest cell survival

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Marshall Lukacs ◽  
Tia Roberts ◽  
Praneet Chatuverdi ◽  
Rolf W Stottmann
Keyword(s):  
Neural Crest ◽  
Heart Development ◽  
Cleft Lip ◽  
Cleft Lip And Palate ◽  
Neural Crest Cell ◽  
Neural Tube Closure ◽  
Specific Expression ◽  
Pathogenic Variants ◽  
Median Cleft ◽  
Cleft Lip Palate

Glycosylphosphatidylinositol (GPI) anchors attach nearly 150 proteins to the cell membrane. Patients with pathogenic variants in GPI biosynthesis genes develop diverse phenotypes including seizures, dysmorphic facial features and cleft palate through an unknown mechanism. We identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypo-morphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2), a component of the GPI biosynthesis pathway. The Clpex mutation decreases surface GPI expression. Surprisingly, Pgap2 showed tissue-specific expression with enrichment in the brain and face. We found the Clpex phenotype is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium. We showed folinic acid supplementation in utero can partially rescue the cleft lip phenotype. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency. These mutants developed median cleft lip and palate demonstrating a previously undocumented cell autonomous role for GPI biosynthesis in NCC development.

scholarly journals Cleft lip and cleft palate (CL/P) in Esrp1 KO mice is associated with alterations in Wnt signaling and epithelial-mesenchymal crosstalk

2019 ◽  
Author(s):  
SungKyoung Lee ◽  
Matthew J. Sears ◽  
Zijun Zhang ◽  
Hong Li ◽  
Imad Salhab ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cleft Palate ◽  
Wnt Signaling ◽  
Cleft Lip ◽  
Wnt Signaling Pathway ◽  
Altered Expression ◽  
Molecular Events ◽  
The Face ◽  
Total Gene Expression ◽  
Embryonic Ectoderm

ABSTRACTCleft lip is one of the most highly prevalent birth defects in human patients. However, there remain a limited number of mouse models of cleft lip and thus much work is needed to further characterize genes and mechanisms that lead to this disorder. It is well established that crosstalk between epithelial and mesenchymal cells underlies formation of the face and palate, yet the basic molecular events mediating this crosstalk are still poorly understood. We previously demonstrated that mice with ablation of the epithelial-specific splicing factor Esrp1 have fully penetrant bilateral CL/P. In this study we further investigated the mechanisms by which ablation of Esrp1 leads to cleft lip as well as cleft palate. These studies included a detailed analysis of the changes in splicing and total gene expression in embryonic ectoderm during formation of the face as well as gene expression changes in adjacent mesenchyme. We identified altered expression in components of pathways previously implicated in cleft lip and/or palate, including numerous components of the Wnt signaling pathway. These findings illustrate that maintenance of an Esrp1 regulated epithelial splicing program is essential for face development through regulation of key signaling pathways.

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