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First published online 6 October 2004
doi: 10.1242/dev.01430

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Id4 regulates neural progenitor proliferation and differentiation in vivo

Kyuson Yun^1,2,*, Akio Mantani^1,*,, Sonia Garel², John Rubenstein² and Mark A. Israel^1,

¹ Department of Pediatrics and Genetics and the Norris Cotton Cancer Center, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA
² Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, LPPI, University of California, 401 Parnassus, Box 0984, San Francisco, CA 94143-0984, USA

View larger version (67K): [in a new window]   Fig. 1. (A) The recombinant targeting construct used to generate a mutant mouse with a disrupted Id4 locus, and a Southern blot and PCR analysis demonstrating the successful targeting event. (B) E15.5 Id4 mutant brain (right) and a littermate wild-type control brain (left). (C,C') Cresyl violet-stained coronal sections through E12.5 wild-type and mutant telencephalon. Measurements of neocortex and hippocampal primordium shown in Fig. 2 were made between the arrows shown. Also, the thickening of the neocortex in the mutant (C') is indicated by a comparison of the length of the black bar (wild-type thickness) to the yellow bar (mutant thickness). Basal ganglia (LGE and MGE) of the mutant appear normal in size. (D,D') E18.5 saggital sections of control (D) and Id4-/- (D') telencephalon stained with cresyl violet. (E-H) Quantitation of the cortical VZ surface areas at E11.5, E12.5 and E15.5, in control and Id4-/- littermates at matched levels on coronal sections (E,F) and saggital sections (G,H), normalized to littermate controls. Yellow bar, Id4+/–; blue bar, Id4-/-; wt, wild type; mt, mutant; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; hp, hippocampus; ctx, neocortex; OB, olfactory bulb; st, striatum; LV, lateral ventricle.

View larger version (125K): [in a new window]   Fig. 2. E11.5 coronal sections through wild-type (A-F) and Id4-/- (A'-F') telencephalon. Wnt3a, Dbx1, Emx1 and Tbr2 expression in LP and VP progenitor zones appears normal (A-D'). (A-B') The limits of the Wnt3a and Dbx1 expression domains are indicated by the arrowheads. (C,C') Arrowheads indicate mantle expression of Emx1 in the lateral pallium. (D') Arrowhead indicates ectopic Tbr2-expressing cells in the VZ; arrow points to the increased number of Tbr2-expressing postmitotic cells in the dorsomedial mantle of the Id4-/- animal. (E) Endogenous Id2 expression shows a ventral-to-dorsal gradient of expression and is undetectable between the arrowheads. (E') The boundaries of the reduced Id2-negative region in the Id4-/- brain is indicated by arrowheads. (F) Id4 expression is uniformly high in all cortical areas. (F') GFP expression from the Id4 locus is detectable in the Id4-/- brain (arrowhead). LGE, lateral ganglionic eminence; VP, ventral pallium; LP, lateral pallium; DP, dorsal pallium; MP, medial pallium; ctx, neocortex; LV, lateral ventricle.

View larger version (89K): [in a new window]   Fig. 3. E11.5 (A,A'), E12.5 (B-C'), E15.5 (D,D') and E18.5 (E-F') coronal (A-D') and saggital (E-F') sections of wild-type (A-F) and Id4-/- (A'-F') telencephalon are compared. Immunofluorescence was detected using the antibodies listed above each panel (A,A',D-E') and in situ hybridization was performed using the S-35-labeled riboprobes listed above each panel (B-C',F,F'). A pan-neuronal marker, MAP2 (A,A'), shows reproducibly increased expression in the mutant dorsomedial cortex (arrowhead). Markers of differentiating neurons, NeuroD (C,C') and Tbr2 (see Fig. 2D,D'), also show increased expression in the dorsomedial mantle (arrowheads in C,C'). TBR1 expression marks differentiating cortical neurons that will form deep cortical layers (D-E'). Arrowheads in F,F' indicate disorganized cortical layers and areas. hp, hippocampus; ctx, neocortex; LV, lateral ventricle; VP, ventral pallium; st, striatum.

View larger version (120K): [in a new window]   Fig. 4. E12.5 (A-C',D') and E15.5 (E-H') coronal sections through control (A-H) and Id4-/- (A'-H') mutant cortex. Markers of cell cycle used are: proliferating cells, PCNA (A,A',D'); S-phase, BrdU pulse (B,B',H,H'); and M-phase, PH3 (C,C',G,G'). (B,B') The G-phase zone is indicated by the distance between the arrowheads; yellow dashes indicate the ventricular surface. (D') High magnification image of PCNA staining (red), double labeled with DAPI (blue) to visualize all nuclei. At E15.5, ectopically positioned Ngn2- and NeuroD-expressing cells were detected outside of the VZ and SVZ (arrowheads in E',F'). Immunofluorescence analysis was performed using antibodies against PH3 and BrdU (following a 45-minute labelling pulse) in littermate control and Id4 null animals (arrowheads in G',H' indicate ectopically proliferating cells). BrdU is shown in green and DAPI in blue (H,H'). Arrow in H' indicates increased BrdU labeling in the Id4-/- SVZ at E15.5. LV, lateral ventricle; hp, hippocampus; ctx, neocortex; LGE, lateral ganglionic eminence; CGE, caudal ganglionic eminence; VZ, ventricular zone; SVZ, subventricular zone.

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