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First published online 12 September 2007
doi: 10.1242/dev.006627

Development 134, 3615-3625 (2007)
Published by The Company of Biologists 2007
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Fgf3 is required for dorsal patterning and morphogenesis of the inner ear epithelium

Ekaterina P. Hatch, C. Albert Noyes, Xiaofen Wang, Tracy J. Wright and Suzanne L. Mansour*

Department of Human Genetics, University of Utah, Salt Lake City, UT 84112-5330, USA.


Figure 1
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  		Fig. 1. Fgf3 alleles and adult phenotypes. (A) Depiction of wild-type (Fgf3+), original (Fgf3neo) and newly targeted (Fgf3{Delta}2) Fgf3 alleles. Solid lines, mouse genomic Fgf3 DNA; open boxes, untranslated regions; solid boxes, protein-coding regions; gray box, MC1Neo cassette. (B) Genotypes at weaning of Fgf3+/neo and Fgf3+/{Delta}2 intercrosses. Numbers and percentage of total (in parentheses) for wild-type (+/+), heterozygous (+/neo or +/{Delta}2) and homozygous (neo/neo or {Delta}2/{Delta}2; photographs to the right) offspring are shown. (C) Auditory brainstem response (ABR) thresholds of Fgf3+/{Delta}2 intercross offspring. Average thresholds (in decibels sound pressure level) for left (L, blue) and right (R, red) ears of +/+ (n=7) and +/{Delta}2 (n=12) animals are shown as boxes; bars indicate one standard deviation. Homozygous mutant ({Delta}2/{Delta}2) ABR measurements are presented as connected circles (left, blue; right, red) for individual animals, with numbers in parentheses indicating the total number of mutant animals with the specified phenotype. Low (D,E) and high (D',E') magnification views of Hematoxylin and Eosin-stained mid-modiolar sections of Fgf3+/{Delta}2 (hearing, D,D') and Fgf3{Delta}2/{Delta}2 (deaf, E,E') ears. oC, organ of Corti; sv, stria vascularis; tm, tectorial membrane. Scale bars: 50 µm.

 

Figure 2
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  		Fig. 2. The morphologies of Fgf3 mutant inner ears fall into types of increasing severity. Lateral views of paint-filled inner ears from E15.5 control (A,B) and Fgf3 mutant (C-I) mice. The percentage of each type among total mutants is indicated at the upper right. Asterisks and star (in I) indicate expected locations of missing structures. Ear side indicated by R (right) and L (left). Structures are labeled in the control left ear (A): aa, anterior ampulla; asc, anterior semicircular canal; cc, common crus; cd, cochlear duct; ed, endolymphatic duct; es, endolymphatic sac; la, lateral ampulla; lsc, lateral semicircular canal; pa, posterior ampulla; psc, posterior semicircular canal; s, saccule; u, utricle.

 

Figure 3
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  		Fig. 3. Fgf3 expression in tissues relevant for inner ear development. (A-L) Whole-mount mouse embryos probed with Fgf3 and sectioned transversely. (A,E,I,J) Lateral views, somite numbers indicated at the lower left. (B,F) Dorsal views. Lines in B,F,J indicate the locations of sections C,D,G,H,K,L as labeled. r, hindbrain rhombomere; ov, otic vesicle; og, otic ganglion; ed, endolymphatic duct.

 

Figure 4
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  		Fig. 4. Dorsal otic gene expression is markedly affected in Fgf3 mutants after E9.5. Mouse embryos probed with Gbx2 (A-D), Dlx5 (E-H), Wnt2b (I,J) or Hmx3 (K,L) were sectioned transversely (A'-L') at the locations indicated by the white lines in A-L. Stage and genotype of each embryo are indicated at the lower left and right, respectively, of each whole-mount panel. ov, otic vesicle; nt, neural tube.

 

Figure 5
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  		Fig. 5. Ventral otic markers are unaffected in Fgf3 mutants. Whole-mount mouse embryos were probed with Pax2 (A,B,C,D) or Otx2 (E,F) and sectioned transversely (A'-F') at the locations indicated by the white lines in A-F. Embryo stages and genotype abbreviations as for Fig. 4.

 

Figure 6
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  		Fig. 6. Sensory and ganglion markers are affected in E10.5 Fgf3 mutants. Whole-mount mouse embryos were probed with Lfng (A,B), Bmp4 (C,D) and Fgf10 (E,F) and sectioned transversely (A'-F', anterior sections; A''-F'', posterior sections) at the locations indicated by the white lines in A-F. Arrowheads point to posterior expression domains of Bmp4 (C,D) and Fgf10 (E,F). Right and left ears in F' and F'' are photographed separately owing to different sectioning angles. Brackets in E' and F' indicate the position of GVIII. Embryo stages and genotype abbreviations as for Fig. 4.

 

Figure 7
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  		Fig. 7. Hindbrain expression of Wnt3a, but not Wnt1, expands ventrally in r5-6 of Fgf3 mutants. Whole-mount mouse embryos were probed with Wnt1 (A,B) or Wnt3a (C,D) and sectioned transversely (A',B', Wnt1; C',D', Wnt3a anterior; C'',D'', Wnt3a central; C''',D''', Wnt3a posterior) at the locations indicated by the labeled white lines in A-D. Embryo stages and genotype abbreviations as for Fig. 4.

 

Figure 8
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  		Fig. 8. Model for FGF3 function in otic morphogenesis initiation. Oblique view of the developing hindbrain and otic vesicle during initiation of otic morphogenesis. The model integrates present data with those published previously. Otic vesicle molecular patterning and morphogenesis are initiated by WNT signals provided redundantly by roofplate-expressed Wnt3a and Wnt1 (dark blue). This signal induces otic Gbx2, which in turn induces Wnt2 and Dlx5 at a minimum, and is required for dorsal outgrowth of the EDS anlage. Fgf3, induced in r5-6 by Hoxa1 and Mafb [Mafb (Kr)], serves to maintain otic Gbx2 and its downstream genes, but has no direct effect on ventral otic genes (Pax2 and Otx2). In addition, Fgf3 prevents medial expansion of otic Hmx3 and ventral expansion of hindbrain Wnt3a. The role of sonic hedgehog (SHH) in ventral otic patterning via induction of Pax2 and Otx2 is illustrated, but was not addressed here.

 




© The Company of Biologists Ltd 2007