High-resolution spatial transcriptomics and cell lineage analysis reveal spatiotemporal cell fate determination during craniofacial development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE293181 | GEO | 2025/04/09
REPOSITORIES: GEO
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Project description:Craniofacial development and neural crest specification are evolutionarily conserved processes, yet subtle modifications to their gene regulatory networks drive species-specific craniofacial diversity. Transposable elements (TEs) are increasingly recognized as contributors to genome evolution, but their role in shaping neural crest regulatory programs remains underexplored. Here, we investigate the domestication of hominoid-specific TEs as enhancers during cranial neural crest cell (CNCC) specification, a process critical for vertebrate head development. Using human iPSC-derived CNCCs, we identified ~250 human-specific TEs, half of which human-specific, acting as active enhancers. These TEs were predominantly LTR5Hs and, to a lesser extent, SVAs. We demonstrate that these elements have been co-opted through the acquisition of a conserved CNCC coordinator motif and are bound by the CNCC signature factor TWIST1, and that their co-option is largely specific to the CNCC cell type. To assess their functional relevance, we used CRISPR-interference to repress ~75% of all the LTR5Hs and SVAs active in CNCCs, leading to widespread transcriptional changes in genes associated with neural crest migration, a process essential for CNCCs to populate the embryo and form craniofacial structures. Using functional assays, we showed that CNCC migration was significantly impaired by CRISPR-mediated TE repression. We further demonstrated that genes near human-specific TEs are more highly expressed in human CNCCs relative to chimpanzee, but TE repression returns their expression to chimpanzee levels. These findings reveal how TEs have been repeatedly co-opted to fine-tune CNCC regulatory networks, shaping lineage-specific craniofacial traits. By integrating evolutionary and developmental perspectives, our study highlights how TEs contribute to regulatory innovations in an otherwise deeply conserved developmental program.
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Project description:The overall goal of this project is to investigate the role of TGF-beta signaling in tissue-tissue interactions between myogenic precursors of craniofacial muscles and cranial neural crest cells (CNCCs). Here, we conducted gene expression profiling of the tongue bud from mice at embryonic day E13.5 with a CNCC-specific conditional inactivation of the TGF-beta receptor type 1 gene Alk5. These mice provide a model of microglossia as well as disrupted extraocular and masticatory muscle development, which are congenital birth defects commonly observed in several syndromic conditions. To investigate the adverse effects of dysfunctional TGF-beta signaling on tissue-tissue interactions between CNCCs and myogenic precursors of craniofacial muscles, we analyzed tongue bud tissue of mice with a CNCC-specific conditional inactivation of Alk5 (Wnt1-Cre; Alk5 fl/fl). We performed microarray analyses of the tongue bud of Alk5 fl/fl control mice and Wnt1-Cre; Alk5 fl/fl mutant mice, collected at embryonic day E13.5 (n=4 per group).
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Project description:The overall goal of this project is to investigate the role of TGF-beta signaling in tissue-tissue interactions between myogenic precursors of craniofacial muscles and cranial neural crest cells (CNCCs). Here, we conducted gene expression profiling of the mandibular arch from mice at embryonic day E11.5 with a CNCC-specific conditional inactivation of the TGF-beta receptor type 1 gene Alk5. These mice provide a model of microglossia as well as disrupted extraocular and masticatory muscle development, which are congenital birth defects commonly observed in several syndromic conditions. To investigate the adverse effects of dysfunctional TGF-beta signaling on tissue-tissue interactions between CNCCs and myogenic precursors of craniofacial muscles, we analyzed mandibular arch tissue of mice with a CNCC-specific conditional inactivation of Alk5 (Wnt1-Cre; Alk5 fl/fl). We performed microarray analyses of the mandibular arch of Alk5 fl/fl control mice and Wnt1-Cre; Alk5 fl/fl mutant mice, collected at embryonic day E11.5 (n=4 per group).
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Project description:Enhancer-promoter interactions preferentially occur within boundary-insulated topologically associating domains (TADs), limiting inter-TAD interactions. Enhancer clusters in linear proximity, termed super-enhancers (SEs), ensure high target gene expression levels. Little is known about SE topological regulatory impact during craniofacial development. Here, we identified 2232 genome-wide putative SEs in mouse cranial neural crest cells (CNCCs), 147 of which target genes establishing CNCC positional identity during face formation. In second pharyngeal arch (PA2) CNCCs, a multiple SE-containing region, partitioned into Hoxa Inter-TAD Regulatory Element 1 and 2 (HIRE1 and HIRE2), establishes long-range inter-TAD interactions selectively with Hoxa2, that is required for external and middle ear structures. HIRE2 deletion in a Hoxa2 haploinsufficient background results in microtia. HIRE1 deletion phenocopies the full homeotic Hoxa2 knockout phenotype and induces PA3 and PA4 CNCC abnormalities correlating with Hoxa2 and Hoxa3 transcriptional downregulation. Thus, SEs can overcome TAD insulation and regulate anterior Hoxa gene collinear expression in a CNCC subpopulation-specific manner during craniofacial development.
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