Try a new search

Format these results:

Searched for:


Total Results:


The Society for Craniofacial Genetics and Developmental Biology 45th Annual Meeting

Stottmann, Rolf W; Harris, Matthew P; Saint-Jeannet, Jean-Pierre; Merrill, Amy E; Clouthier, David E
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 45th Annual Meeting at the Sanford Consortium for Regenerative Medicine at the University of California, San Diego on October 20th-21st, 2022. The meeting included presentation of the SCGDB Distinguished Scientists in Craniofacial Research Awards to Drs. Ralph Marcucio and Loydie Jerome-Majewska and four scientific sessions that highlighted new discoveries in signaling in craniofacial development, genomics of craniofacial development, human genetics of craniofacial development and translational and regenerative approaches in craniofacial biology. The meeting also included workshops on analysis of single cell RNA sequencing datasets and using human sequencing data from the Gabriella Miller Kids First Pediatric Research Program. There were 110 faculty and trainees in attendance that represent a diverse group of researchers from all career stages in the fields of developmental biology and genetics. The meeting, which also included outdoor poster presentations, provided opportunities for participant interactions and discussions, thus strengthening the SCGDB community.
PMID: 37040531
ISSN: 1552-4833
CID: 5464132

The Core Splicing Factors EFTUD2, SNRPB and TXNL4A Are Essential for Neural Crest and Craniofacial Development

Park, Byung-Yong; Tachi-Duprat, Melanie; Ihewulezi, Chibuike; Devotta, Arun; Saint-Jeannet, Jean-Pierre
Mandibulofacial dysostosis (MFD) is a human congenital disorder characterized by hypoplastic neural-crest-derived craniofacial bones often associated with outer and middle ear defects. There is growing evidence that mutations in components of the spliceosome are a major cause for MFD. Genetic variants affecting the function of several core splicing factors, namely SF3B4, SF3B2, EFTUD2, SNRPB and TXNL4A, are responsible for MFD in five related but distinct syndromes known as Nager and Rodriguez syndromes (NRS), craniofacial microsomia (CFM), mandibulofacial dysostosis with microcephaly (MFDM), cerebro-costo-mandibular syndrome (CCMS) and Burn-McKeown syndrome (BMKS), respectively. Animal models of NRS and MFDM indicate that MFD results from an early depletion of neural crest progenitors through a mechanism that involves apoptosis. Here we characterize the knockdown phenotype of Eftud2, Snrpb and Txnl4a in Xenopus embryos at different stages of neural crest and craniofacial development. Our results point to defects in cranial neural crest cell formation as the likely culprit for MFD associated with EFTUD2, SNRPB and TXNL4A haploinsufficiency, and suggest a commonality in the etiology of these craniofacial spliceosomopathies.
PMID: 35893124
ISSN: 2221-3759
CID: 5277152

The Society for Craniofacial Genetics and Developmental Biology 44th Annual Meeting

Brugmann, Samantha A; Merrill, Amy E; Saint-Jeannet, Jean-Pierre; Stottmann, Rolf W; Clouthier, David E
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 44th Annual Meeting in a virtual format on October 18-19, 2021. The SCGDB meeting included presentation of the SCGDB Distinguished Scientists in Craniofacial Research Awards to Drs. Paul Trainor and Jeff Bush and four scientific sessions on the genomics of craniofacial development, craniofacial morphogenesis and regeneration, translational craniofacial biology and signaling during craniofacial development. The meeting also included workshops on professional development for faculty and trainees, National Institutes of Health (NIH)/National Institute of Craniofacial and Dental Research funding and usage of Genomics Software, as well as two poster sessions. An exhibitor booth run by FaceBase was also present to facilitate the upload and download of datasets relevant to the craniofacial community. Over 200 attendees from 12 countries and 23 states, representing over 80 different scientific institutions, participated. This diverse group of scientists included cell biologists, developmental biologists, and clinical geneticists. Although the continuing COVID-19 pandemic forced a virtual meeting format for a second year in a row, the meeting platform provided ample opportunities for participant interactions and discussions, thus strengthening the community.
PMID: 35352468
ISSN: 1552-4833
CID: 5220142

Anterior patterning genes induced by Zic1 are sensitive to retinoic acid and its metabolite, 4-oxo-RA

Dubey, Aditi; Saint-Jeannet, Jean-Pierre
BACKGROUND:Development of paired sensory organs is a highly complex and coordinated process. These organs arise from ectodermal thickenings in the cephalic region known as cranial placodes. We have previously shown that Zic1 is a critical regulator for the formation of the pre-placodal region (PPR), the common territory for the development of all cranial placodes in Xenopus laevis. RESULTS:In this study, we have analyzed a number of Zic1 targets for their expression during PPR patterning, as well as their regulation by retinoic acid (RA) and one of its major metabolites, 4-oxo-RA. Our findings show that anteriorly Zic1 regulates several transcription factors, Crx, Fezf2, Nkx3-1, and Xanf1 as well as a serine/threonine/tyrosine kinase, Pkdcc.2. These factors are all expressed in the vicinity of the PPR and as such are candidate regulators of placode formation downstream of Zic1. In addition to their differential regulation by RA, we find that 4-oxo-RA is also capable of modulating the expression of these genes, as well as a broad array of RA-regulated genes. CONCLUSION/CONCLUSIONS:Our data highlight the complexity of retinoid-mediated regulation required for Zic1-activated anterior structure specification in Xenopus, and the potential physiological role of 4-oxo-RA in cranial placode development.
PMID: 34536327
ISSN: 1097-0177
CID: 5012482

Xbp1 and Brachyury establish an evolutionarily conserved subcircuit of the notochord gene regulatory network

Wu, Yushi; Devotta, Arun; José-Edwards, Diana S; Kugler, Jamie E; Negrón-Piñeiro, Lenny J; Braslavskaya, Karina; Addy, Jermyn; Saint-Jeannet, Jean-Pierre; Di Gregorio, Anna
Gene regulatory networks coordinate the formation of organs and structures that compose the evolving body plans of different organisms. We are using a simple chordate model, the Ciona embryo, to investigate the essential gene regulatory network that orchestrates morphogenesis of the notochord, a structure necessary for the proper development of all chordate embryos. Although numerous transcription factors expressed in the notochord have been identified in different chordates, several of them remain to be positioned within a regulatory framework. Here, we focus on Xbp1, a transcription factor expressed during notochord formation in Ciona and other chordates. Through the identification of Xbp1-downstream notochord genes in Ciona, we found evidence of the early co-option of genes involved in the unfolded protein response to the notochord developmental program. We report the regulatory interplay between Xbp1 and Brachyury, and by extending these results to Xenopus, we show that Brachyury and Xbp1 form a cross-regulatory subcircuit of the notochord gene regulatory network that has been consolidated during chordate evolution.
PMID: 35049502
ISSN: 2050-084x
CID: 5157112

Function of chromatin modifier Hmgn1 during neural crest and craniofacial development

Ihewulezi, Chibuike; Saint-Jeannet, Jean-Pierre
The neural crest is a dynamic embryonic structure that plays a major role in the formation of the vertebrate craniofacial skeleton. Neural crest formation is regulated by a complex sequence of events directed by a network of transcription factors working in concert with chromatin modifiers. The high mobility group nucleosome binding protein 1 (Hmgn1) is a nonhistone chromatin architectural protein, associated with transcriptionally active chromatin. Here we report the expression and function of Hmgn1 during Xenopus neural crest and craniofacial development. Hmgn1 is broadly expressed at the gastrula and neurula stages, and is enriched in the head region at the tailbud stage, especially in the eyes and the pharyngeal arches. Hmgn1 knockdown affected the expression of several neural crest specifiers, including sox8, sox10, foxd3, and twist1, while other genes (sox9 and snai2) were only marginally affected. The specificity of this phenotype was confirmed by rescue, where injection of Hmgn1 mRNA was able to restore sox10 expression in morphant embryos. The reduction in neural crest gene expression at the neurula stage in Hmgn1 morphant embryos correlated with a decreased number of sox10- and twist1-positive cells in the pharyngeal arches at the tailbud stage, and hypoplastic craniofacial cartilages at the tadpole stage. These results point to a novel role for Hmgn1 in the control of gene expression essential for neural crest and craniofacial development. Future work will investigate the precise mode of action of Hmgn1 in this context.
PMID: 34478234
ISSN: 1526-968x
CID: 4999392

Haploinsufficiency of SF3B2 causes craniofacial microsomia

Timberlake, Andrew T; Griffin, Casey; Heike, Carrie L; Hing, Anne V; Cunningham, Michael L; Chitayat, David; Davis, Mark R; Doust, Soghra J; Drake, Amelia F; Duenas-Roque, Milagros M; Goldblatt, Jack; Gustafson, Jonas A; Hurtado-Villa, Paula; Johns, Alexis; Karp, Natalya; Laing, Nigel G; Magee, Leanne; Mullegama, Sureni V; Pachajoa, Harry; Porras-Hurtado, Gloria L; Schnur, Rhonda E; Slee, Jennie; Singer, Steven L; Staffenberg, David A; Timms, Andrew E; Wise, Cheryl A; Zarante, Ignacio; Saint-Jeannet, Jean-Pierre; Luquetti, Daniela V
Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10-10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
PMID: 34344887
ISSN: 2041-1723
CID: 4988632

The society for craniofacial genetics and developmental biology 43rd annual meeting

Brugmann, Samantha; Clouthier, David E; Saint-Jeannet, Jean-Pierre; Taneyhill, Lisa A; Moody, Sally A
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 43rd annual meeting in a virtual format on October 19-20, 2020. The SCGDB meeting included the presentation of the SCGDB Distinguished Scientists in Craniofacial Research Awards to Marilyn Jones and Kerstin Ludwig and four scientific sessions on the molecular regulation of craniofacial development, craniofacial morphogenesis, translational craniofacial biology, and signaling during craniofacial development. The meeting also included workshops on career development, NIH/NIDCR funding, and the utility of the FaceBase database, as well as two poster sessions. Over 190 attendees from 21 states, representing over 50 different scientific institutions, participated. This diverse group of scientists included cell biologists, developmental biologists, and clinical geneticists. While in-person interactions were missed due to the virtual meeting format imposed by the COVID-19 pandemic, the meeting platform provided ample opportunities for participant interactions and discussions, thus strengthening the community.
PMID: 33660912
ISSN: 1552-4833
CID: 4889552

Molecular mechanisms of hearing loss in Nager syndrome

Maharana, Santosh Kumar; Saint-Jeannet, Jean-Pierre
Nager syndrome is a rare human developmental disorder characterized by hypoplastic neural crest-derived craniofacial bones and limb defects. Mutations in SF3B4 gene, which encodes a component of the spliceosome, are a major cause for Nager. A review of the literature indicates that 45% of confirmed cases are also affected by conductive, sensorineural or mixed hearing loss. Conductive hearing loss is due to defective middle ear ossicles, which are neural crest derived, while sensorineural hearing loss typically results from defective inner ear or vestibulocochlear nerve, which are both derived from the otic placode. Animal model of Nager syndrome indicates that upon Sf3b4 knockdown cranial neural crest progenitors are depleted, which may account for the conductive hearing loss in these patients. To determine whether Sf3b4 plays a role in otic placode formation we analyzed the impact of Sf3b4 knockdown on otic development. Sf3b4-depleted Xenopus embryos exhibited reduced expression of several pan-placodal genes six1, dmrta1 and foxi4.1. We confirmed the dependence of placode genes expression on Sf3b4 function in animal cap explants expressing noggin, a BMP antagonist critical to induce placode fate in the ectoderm. Later in development, Sf3b4 morphant embryos had reduced expression of pax8, tbx2, otx2, bmp4 and wnt3a at the otic vesicle stage, and altered otic vesicle development. We propose that in addition to the neural crest, Sf3b4 is required for otic development, which may account for sensorineural hearing loss in Nager syndrome.
PMID: 33864777
ISSN: 1095-564x
CID: 4871902

Retinoic acid production, regulation, and containment through Zic1, Pitx2c and Cyp26c1 control cranial placode specification

Dubey, Aditi; Yu, Jianshi; Liu, Tian; Kane, Maureen A; Saint-Jeannet, Jean-Pierre
All paired sensory organs arise from a common precursor domain called the pre-placodal region (PPR). In Xenopus, Zic1 non-cell autonomously regulates PPR formation by activating retinoic acid (RA) production. Here we identified two Zic1 targets, the RA catabolizing enzyme Cyp26c1 and the transcription factor Pitx2c, expressed in the vicinity of the PPR as crucially required for maintaining low RA levels in a spatially restricted, PPR-adjacent domain. Morpholino- or CRISPR/Cas9-mediated Cyp26c1 knockdown abrogated PPR gene expression, yielding defective cranial placodes. Direct measurement of RA levels revealed that this is mediated by a mechanism involving excess RA accumulation. Furthermore, we show that pitx2c is activated by RA and required for Cyp26c1 expression in a domain-specific manner through induction of FGF8. We propose that Zic1 anteriorly establishes a program of RA containment and regulation through activation of Cyp26c1 and Pitx2c that cooperates to promote PPR specification in a spatially restricted domain.
PMID: 33531433
ISSN: 1477-9129
CID: 4777122