PUBLICATION

ALX1-related frontonasal dysplasia results from defective neural crest cell development and migration

Authors
Pini, J., Kueper, J., Hu, Y.D., Kawasaki, K., Yeung, P., Tsimbal, C., Yoon, B., Carmichael, N., Maas, R.L., Cotney, J., Grinblat, Y., Liao, E.C.
ID
ZDB-PUB-201002-21
Date
2020
Source
EMBO Molecular Medicine   12(10): e12013 (Journal)
Registered Authors
Grinblat, Yevgenya, Liao, Eric
Keywords
iPSC, ALX1, frontonasal dysplasia, neural crest cells, zebrafish
MeSH Terms
  • Animals
  • Cell Movement
  • Craniofacial Abnormalities*/genetics
  • Face/abnormalities
  • Humans
  • Neural Crest*
  • Zebrafish
PubMed
32914578 Full text @ EMBO Mol. Med.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes