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First published online 21 July 2004
doi: 10.1242/dev.01272

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The homeobox gene Gsh2 is required for retinoid production in the embryonic mouse telencephalon

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA

View larger version (77K): [in a new window]   Fig. 1. Altered expression of Raldh3 detected by immunohistochemistry (IHC) in Gsh2 mutants. (A) At E12.5, Raldh3 is normally expressed in the SVZ of the ventromedial LGE. (B) In Gsh2 mutants, the Raldh3 staining is reduced and its normal expression domain in the LGE is truncated (arrow). However, the expression of Raldh3 in the nasal epithelium (NE) and retina (R) remains at wild-type levels. (C) At E16.5, Raldh3 is expressed in the SVZ of the LGE and septum, and (D) remains severely reduced in the Gsh2 mutant LGE. NE, nasal epithelium; R, retina; Stm, striatum.

View larger version (54K): [in a new window]   Fig. 2. Gsh2 mutants exhibit reduced retinoid production in the ventral telencephalon. (A-C) Representative pictures of X-gal-positive F9 cells, stably transfected with RARE-lacZ, that were co-cultured for 24 hours with E12.5 LGE explants from wild-type embryos (A), Gsh2 heterozygotes (het, B) or Gsh2 homozygous mutants (KO, C). (D,E) Bar graphs showing the reduced numbers of X-gal-positive cells from LGE (black bars) or MGE (white bars) explants at E12.5 (D), and LGE (black bars) or cortex (white bars) at E16.5 (E). *P<0.05, **P<0.01, one-way ANOVA using a Fisher test as a post-hoc. E12.5, n=4 WT, 12 +/– and 6 –/–; E16.5, n=3 WT, 15 +/– and 5 –/–.

View larger version (84K): [in a new window]   Fig. 3. Reduced Raldh3 expression detected by IHC in Gsh2 mutants is independent of ectopic Pax6. The Raldh3 expression domain appears normal in the Pax6 mutant LGE (compare arrow in A with the wild type in Fig. 1A). However, Raldh3 expression in the Pax6;Gsh2 double mutant LGE is truncated, similar to that in the Gsh2 mutant LGE (compare arrow in B to that in Fig. 1B).

View larger version (78K): [in a new window]   Fig. 4. The altered DARPP-32 expression detected by IHC in Gsh2 mutants is independent of ectopic Pax6. Foxp1, a marker of the developing striatal neurons during development (A), appears relatively normal in a Pax6 mutant striatum (C). The number of Foxp1-expressing cells (detected by IHC) is severely reduced in the Gsh2 mutant striatum (B), which is improved by removing Pax6 from the Gsh2 mutant background (i.e. in Pax6;Gsh2 double mutants) (D). Gsh2 mutants (F) exhibit a disproportionate reduction in the number of DARPP-32-positive neurons compared with wild type (E) and Pax6 mutants (G). Despite the improvement in striatal size in Pax6;Gsh2 double mutants, the number of DARPP-32-positive neurons remains disproportionately reduced (H), similar to that in the Gsh2 mutant (F).

View larger version (119K): [in a new window]   Fig. 5. Gsh2 mutants maintain expression of the RAR/RXR heterodimer in the differentiating striatum. Rarb (A) and Rxrg (C) genes are expressed in the differentiating striatal neurons at E16.5 (in situ hybridization detection). Gsh2 mutants maintain expression of both Rarb (B) and Rxrg (D); however, the domain of expression is reduced in accordance with the reduction in size of the mutant striatum. Stm, striatum.

View larger version (91K): [in a new window]   Fig. 6. Exogenous retinoids improve striatal neuron differentiation in the Gsh2 mutant. At E18.5, DARPP-32 expression (detected by IHC) is increased at all levels of the striatum in the RA-treated Gsh2 mutants (B,D) compared with vehicle (oil)-treated Gsh2 mutants (A,C). RA treatment of the Gsh2 mutants does not alter striatal size, as marked by Foxp1 staining (F,H). Indeed, the size of the RA-treated striatum appears to be very similar to that of the control oil treatments (E,G). GP, globus pallidus.