Elsevier

Developmental Biology

Volume 458, Issue 2, 15 February 2020, Pages 189-199
Developmental Biology

Nubp2 is required for cranial neural crest survival in the mouse

https://doi.org/10.1016/j.ydbio.2019.10.039Get rights and content
Under an Elsevier user license
open archive

Highlights

  • The ENU mutant dorothy exhibits midfacial clefting, micromelia, and syndactyly.

  • Dorothy is caused by Nubp2:c:626T>A which codes NUBP2:p:Val209Asp (Nubp2dor).

  • Nubp2 is required for organogenesis, Nubp2null/null and Nubp2null/dor are lethal.

  • Midfacial cleft in Wnt1-cre; Nubp2cKO embryos is caused by neural crest apoptosis.

Abstract

The N-ethyl-N-nitrosourea (ENU) ←forward genetic screen is a useful tool for the unbiased discovery of novel mechanisms regulating developmental processes. We recovered the dorothy mutation in such a screen designed to recover recessive mutations affecting craniofacial development in the mouse. Dorothy embryos die prenatally and exhibit many striking phenotypes commonly associated with ciliopathies, including a severe midfacial clefting phenotype. We used exome sequencing to discover a missense mutation in nucleotide binding protein 2 (Nubp2) to be causative. This finding was confirmed by a complementation assay with the dorothy allele and an independent Nubp2 null allele (Nubp2null). We demonstrated that Nubp2 is indispensable for embryogenesis. NUBP2 is implicated in both the cytosolic iron/sulfur cluster assembly pathway and negative regulation of ciliogenesis. Conditional ablation of Nubp2 in the neural crest lineage with Wnt1-cre recapitulates the dorothy craniofacial phenotype. Using this model, we found that the proportion of ciliated cells in the craniofacial mesenchyme was unchanged, and that markers of the SHH, FGF, and BMP signaling pathways are unaltered. Finally, we show evidence that the phenotype results from a marked increase in apoptosis within the craniofacial mesenchyme.

Keywords

Nubp2
Neural crest
ENU mutagenesis
Cilia

Cited by (0)