The spontaneous mouse mutant low set ears (Lse) is caused by tandem duplication of Fgf3 and Fgf4.

Authors

Alana Luzzio, The Jackson Laboratory
Sarah Edie, The Jackson LaboratoryFollow
Kristina Palmer, The Jackson LaboratoryFollow
L Brianna Caddle, The Jackson LaboratoryFollow
Rachel Urban, The Jackson LaboratoryFollow
Leslie Goodwin, The Jackson LaboratoryFollow
Ian C Welsh, The Jackson LaboratoryFollow
Laura G ReinholdtFollow
David E. Bergstrom, The Jackson LaboratoryFollow
Timothy C Cox
Leah Rae DonahueFollow
Stephen A. Murray, The Jackson LaboratoryFollow

Document Type

Article

Publication Date

9-1-2023

Original Citation

Luzzio A, Edie S, Palmer K, Caddle L, Urban R, Goodwin L, Welsh I, Reinholdt L, Bergstrom DE, Cox T, Donahue L, Murray SA. The spontaneous mouse mutant low set ears (Lse) is caused by tandem duplication of Fgf3 and Fgf4. Mamm Genome. 2023;34(3):453-63.

Keywords

JMG, Animals, Mice, Humans, Fibroblast Growth Factors, Mutation, Disease Models, Animal, Polydactyly, Fibroblast Growth Factor 3

JAX Source

Mamm Genome. 2023;34(3):453-63.

ISSN

1432-1777

PMID

37341808

DOI

https://doi.org/10.1007/s00335-023-09999-8

Grant

This work was supported by NIH Grants OD021325 (L.G.R. and D.E.B), EY015073 (L.R.D.), DE020052 (S.A.M. and L.R.D.)

Abstract

The external ear develops from an organized convergence of ventrally migrating neural crest cells into the first and second branchial arches. Defects in external ear position are often symptomatic of complex syndromes such as Apert, Treacher-Collins, and Crouzon Syndrome. The low set ears (Lse) spontaneous mouse mutant is characterized by the dominant inheritance of a ventrally shifted external ear position and an abnormal external auditory meatus (EAM). We identified the causative mutation as a 148 Kb tandem duplication on Chromosome 7, which includes the entire coding sequences of Fgf3 and Fgf4. Duplications of FGF3 and FGF4 occur in 11q duplication syndrome in humans and are associated with craniofacial anomalies, among other features. Intercrosses of Lse-affected mice revealed perinatal lethality in homozygotes, and Lse/Lse embryos display additional phenotypes including polydactyly, abnormal eye morphology, and cleft secondary palate. The duplication results in increased Fgf3 and Fgf4 expression in the branchial arches and additional discrete domains in the developing embryo. This ectopic overexpression resulted in functional FGF signaling, demonstrated by increased Spry2 and Etv5 expression in overlapping domains of the developing arches. Finally, a genetic interaction between Fgf3/4 overexpression and Twist1, a regulator of skull suture development, resulted in perinatal lethality, cleft palate, and polydactyly in compound heterozygotes. These data indicate a role for Fgf3 and Fgf4 in external ear and palate development and provide a novel mouse model for further interrogation of the biological consequences of human FGF3/4 duplication.