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. 2006 Mar 17;311(5767):1609-12.
doi: 10.1126/science.1121449.

alphaE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway

Wen-Hui Lien  1 , Olga Klezovitch, Tania E Fernandez, Jeff Delrow, Valeri Vasioukhin
Affiliations

alphaE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway

Wen-Hui Lien et al. Science. .

Abstract

During development, cells monitor and adjust their rates of accumulation to produce organs of predetermined size. We show here that central nervous system-specific deletion of the essential adherens junction gene, alphaE-catenin, causes abnormal activation of the hedgehog pathway, resulting in shortening of the cell cycle, decreased apoptosis, and cortical hyperplasia. We propose that alphaE-catenin connects cell-density-dependent adherens junctions with the developmental hedgehog pathway and that this connection may provide a negative feedback loop controlling the size of developing cerebral cortex.

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Figures

Fig. 1
Fig. 1
Severe dysplasia and hyperplasia in αE-catenin−/− brain. Histologic appearance of brains from wildtype (WT) and αE-cateninLoxP/LoxP/Nestin-Cre+/− (KO) mice. Sagittal sections through developing telencephalon from the wildtype (A, C) and αE-catenin−/− (A′, C′) brains of E12.5 (A, A′) and E13.5 (C, C′) embryos. Ventricular zone of the cerebral cortex from the E12.5 wildtype (B) and αE-catenin−/− (B′) brains. Coronal sections from the E15.5 wildtype (D, E, F) and αE-catenin−/− (D′, E′, F′) brains. Areas in dashed squares in D, D′ are shown at higher magnification in F, F′. Bar in A′ represents 0.27 mm in A, A′; 0.36 mm in C–C′; 0.42 mm in D, D′; 0.54 mm in E–E′; 50 km in F, F′, 40 km in B, B′.
Fig. 2
Fig. 2
Loss of cell polarity and disruption of apical-junctional complex in αE-catenin−/−neural progenitor cells. (A–F) Disruption of apical adherens junctions in αE-catenin−/− neural progenitors. Staining with anti-N-cadherin (A, D; green in C, F) and anti-αE-catenin (B, E; red in C, F) antibodies. (G–I) Electron microscopy analysis of cortical neural progenitor cells of E12.5 wildtype (G) and αE-catenin−/− (H, I) embryos. Areas in dashed squares in G, H are magnified in insets. Arrowheads in inset to G denote missing in mutants apical-junctional complexes. Arrows indicate internalization of polarized neuroepithelium and formation of rosette-like structures maintaining apical-junctional complexes. Arrowheads in E, F denote blood vessels not targeted by Nestin-Cre. Bar in I corresponds to 30 km in A–F; 10 km in G–H, 4 km in I and 1.8 km in insets to G–H.
Fig. 3
Fig. 3
Shortening of cell cycle and decreased apoptosis in αE-catenin−/− cerebral cortexes. (A) Model of cortical neurogenesis. (B, B′) Minor changes in cell cycle withdrawal in αE-catenin−/− cortexes. Pregnant females were injected with BrdU 24h before being sacrificed. Cells re-entering cell cycle are BrdU+/Ki67+, while cells withdrawn from cell cycle are BrdU+/Ki67−. (C) Quantitation of experiments shown in B-B′. Cell cycle exit is determined as a ratio of cells exited cell cycle (BrdU+/Ki67−) to all cells incorporated BrdU. n=3. (D–E′) Decrease in cell cycle length in αE-catenin−/− progenitors. Higher percentage of αE-catenin−/−progenitor cells (Ki67+) are labeled with BrdU after 30 min pulse. (F) Quantitation of experiments shown in D–E′. BrdU labeling index is a percentage of Ki67+ cells incorporated BrdU. n=3. *P<0.001. (G–H′) Immunostaining of cortical sections from wildtype and αE-catenin−/− brains with anti-phospho-histone 3 (red) antibodies reveals increase in mitotic cells in E13.5 mutants. DNA was counterstained by DAPI (blue). (I) Quantitation of the experiments shown in G–H′. Mitotic index is a ratio of mitotic cells to the total brain cell number. n=3. *P<0.001. (J–K′) Decrease in apoptosis in αE-catenin−/− cortexes. Apoptotic cells in the wildtype (J–K) and mutant (J′–K′) brains were detected by staining with anti-cleaved caspase 3 (Casp3) and TUNEL stainings. (L) Quantitation of experiments shown in J–K′. Ratios of Casp3+ or TUNEL+ cells per total cell numbers are shown. n=3. *P<0.001. Bar in frame K′ represents 100 km for B–B′, D–K′.
Fig. 4
Fig. 4
Activation of Hh pathway is responsible for shortening of cell cycle, decreased apoptosis and subsequent hyperplasia in αE-catenin−/− cerebral cortexes. (A) qPCR analysis of Hh pathway transcripts in E12.5 heterozygous and mutant brains. The levels of expression are shown in arbitrary units with mean heterozygous levels adjusted to one. Data represent means ± SD. N≥4. *P<0.002. (B–D′) Cortical sections from E12.5 wildtype and αE-catenin−/−embryos were analyzed by in situ hybridization with Gli1, Fgf15 and Smo probes. Bar in frame D represents 200km. (E) Inhibition of Hh pathway by cyclopamine eliminates thedifferences in total cell numbers, cell cycle length and apoptosis between the wildtype and αE-catenin−/− brains. Pregnant females were injected with 10mg/kg of cyclopamine in 2-hydropropyl-β-cyclodextrin (vehicle) or vehicle alone at E12.5 and embryos were analyzed 30h later. Quantitation was performed as described in Figs. 3, S2. Data represent means ± SD. N≥3. *P<0.001.
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