ALX1-related frontonasal dysplasia results from defective neural crest cell development and migration.
Jonathan PiniJanina KueperYiyuan David HuKenta KawasakiPan YeungCasey TsimbalBaul YoonNikkola CarmichaelRichard L MaasJustin CotneyYevgenya GrinblatEric C LiaoPublished in: EMBO molecular medicine (2020)
A pedigree of subjects presented with frontonasal dysplasia (FND). Genome sequencing and analysis identified a p.L165F missense variant in the homeodomain of the transcription factor ALX1 which was imputed to be pathogenic. Induced pluripotent stem cells (iPSC) were derived from the subjects and differentiated to neural crest cells (NCC). NCC derived from ALX1L165F/L165F iPSC were more sensitive to apoptosis, showed an elevated expression of several neural crest progenitor state markers, and exhibited impaired migration compared to wild-type controls. NCC migration was evaluated in vivo using lineage tracing in a zebrafish model, which revealed defective migration of the anterior NCC stream that contributes to the median portion of the anterior neurocranium, phenocopying the clinical presentation. Analysis of human NCC culture media revealed a change in the level of bone morphogenic proteins (BMP), with a low level of BMP2 and a high level of BMP9. Soluble BMP2 and BMP9 antagonist treatments were able to rescue the defective migration phenotype. Taken together, these results demonstrate a mechanistic requirement of ALX1 in NCC development and migration.
Keyphrases
- induced pluripotent stem cells
- single cell
- mesenchymal stem cells
- transcription factor
- bone regeneration
- endothelial cells
- oxidative stress
- bone mineral density
- induced apoptosis
- wild type
- stem cells
- gene expression
- dna methylation
- bone marrow
- poor prognosis
- cell proliferation
- body composition
- postmenopausal women
- long non coding rna