Open AccessALX 1‐ related frontonasal dysplasia results from defective neural crest cell development and migration
Author(s) -
Pini Jonathan,
Kueper Janina,
Hu Yiyuan David,
Kawasaki Kenta,
Yeung Pan,
Tsimbal Casey,
Yoon Baul,
Carmichael Nikkola,
Maas Richard L,
Cotney Justin,
Grinblat Yevgenya,
Liao Eric C
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012013
Subject(s) - medicine , general hospital , general surgery
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 ALX 1 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 ALX 1 L165F/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 BMP 2 and a high level of BMP 9. Soluble BMP 2 and BMP 9 antagonist treatments were able to rescue the defective migration phenotype. Taken together, these results demonstrate a mechanistic requirement of ALX 1 in NCC development and migration.