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. 2008 May 6;105(18):6765-70.
doi: 10.1073/pnas.0802109105. Epub 2008 Apr 28.

Modular patterning of structure and function of the striatum by retinoid receptor signaling

Wen-Lin Liao  1 , Hsiu-Chao Tsai, Hsiao-Fang Wang, Josephine Chang, Kuan-Ming Lu, Hsiao-Lin Wu, Yi-Chao Lee, Ting-Fen Tsai, Hiroshi Takahashi, Michael Wagner, Norbert B Ghyselinck, Pierre Chambon, Fu-Chin Liu
Affiliations

Modular patterning of structure and function of the striatum by retinoid receptor signaling

Wen-Lin Liao et al. Proc Natl Acad Sci U S A. .

Abstract

Retinoid signaling plays a crucial role in patterning rhombomeres in the hindbrain and motor neurons in the spinal cord during development. A fundamentally interesting question is whether retinoids can pattern functional organization in the forebrain that generates a high order of cognitive behavior. The striatum contains a compartmental structure of striosome (or "patch") and intervening matrix. How this highly complex mosaic design is patterned by the genetic programs during development remains elusive. We report a developmental mechanism by which retinoid receptor signaling controls compartmental formation in the striatum. We analyzed RARbeta(-/-) mutant mice and found a selective loss of striosomal compartmentalization in the rostral mutant striatum. The loss of RARbeta signaling in the mutant mice resulted in reduction of cyclin E2, a cell cycle protein regulating transition from G(1) to S phase, and also reduction of the proneural gene Mash1, which led to defective neurogenesis of late-born striosomal cells. Importantly, during striatal neurogenesis, endogenous levels of retinoic acid were spatiotemporally regulated such that transduction of high levels of retinoic acid through RARbeta selectively expanded the population of late-born striosomal progenitors, which evolved into a highly elaborate compartment in the rostral striatum. RARbeta(-/-) mutant mice, which lacked such enlarged compartment, displayed complex alternations of dopamine agonist-induced stereotypic motor behavior, including exaggeration of head bobbing movement and reduction of rearing activity. RARbeta signaling thus plays a crucial role in setting up striatal compartments that may engage in neural circuits of psychomotor control.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Aberrant compartments of striosomes and matrix in the adult striatum of RARβ−/− mutant mice. Immunostains of MOR1 (A, A′, B, B′) and calbindin (C, C′, D, D′) show that striosomes, as marked by MOR1-positive neuropil patches (A) and calbindin-poor zones (C), are reduced in the mutant striatum at rostral levels (A′, C′). The bracketed regions in C, C′ are shown at high magnification in E, E′. The areas of MOR1-positive patches are decreased in RARβ−/− mutant mice at the rostral level (F). The striosomal reduction of MOR1 and loss of calbindin-poor zones are less prominent in the mutant striatum at caudal levels (B, B′, D, D′, F). (G) The striatal area was reduced at the rostral but not the caudal level. (H–K) Loss of late-born S cells in RARβ−/− mutant striatum. The bracketed regions in H, H′ are shown at high magnification in I, I′, J, J′. Double immunostaining of MOR1 and BrdU (H–J′) shows that S cells pulse-labeled with BrdU at E12.75 and E13 (darkly stained black nuclei, arrowheads) are typically concentrated in MOR1-positive striosomes (brown neuropil patches, H, I) and the subcallosal lateral streak (H and J) in wild-type striatum. In contrast, only a few darkly stained BrdU-positive S cells (arrowheads) are present in the mutant striatum (H′, I′). BrdU-labeled cells are illustrated at high magnification in Insets (I, I′). Note that BrdU-positive S cells remain in the subcallosal lateral streak of mutant striatum (J′). (K) The number of BrdU-positive S cells is decreased in the striatal proper of mutant striatum but not in the lateral streak. **, P < 0.01, ***, P < 0.001, Student's t test, n = 3. (Scale bars in A for A, A′, 500 μm; in B for B, B′, 500 μm; in C for C, C′, 500 μm; in D for D, D′, 500 μm; in E for E, E′, 200 μm; In H′ for H, H′ 500 μm; in I′ for I–J′, 100 μm.)
Fig. 2.
Fig. 2.
Defective neurogenesis of late-born S cells in striatal anlage of RARβ−/− mutant embryos. (A, A′, C) Twenty-eight hours after a single pulse labeling of BrdU at E12.75, more BrdU-positive S cells (green) migrate into the Ki67-negative differentiated mantle zone (MZ) of wild-type LGE (A) than that in the mutant LGE (A′, C). (B, B′, D, E) The number of S cells pulse-labeled with BrdU for 1 h at E12.75 is reduced in the VZ of LGE but not in the VP (E). The arrowheads in B, B′ indicate the boundary between the LGE and the VP. The reduction of cell proliferation also is temporally specific, because it occurs only in the S progenitor pulse-labeled with BrdU at E12.75 (late-born S cells) but not at E11.5 (early-born S cells; D), nor does it occur in the progenitors of matrix (M) cells pulse-labeled with BrdU at E16.5 (D). (F–I) Reduction of neurogenesis markers in RARβ−/− mutant LGE. Ccne2 mRNA is decreased in the mutant E12.75 LGE and VP (F, F′, H). The VP and the LGE are indicated by the regions between the double and single arrowheads and between the single arrowhead and arrow, respectively, in F, F′. Mash1 mRNA is reduced in E13.5 RARβ−/− mutant LGE (G, G′, I). *, P < 0.05; ***, P < 0.001, Student's t test. All experiments were repeated at least three times. CTX, cortex; Sep, septum; SVZ, subventricular zone; VP, ventral pallium. (Scale bars in A for A, A′; in B for B, B′; in F for F, F′; and in G for G, G′, 100 μm.)
Fig. 3.
Fig. 3.
RA-induced increases of cell proliferation in striatal anlage. Embryos were maternally treated with all-trans RA (5 mg/kg) every 12 h from E10.5 to E11.5 (A, A′, B, B′, E, F) or E12.5 to E13.5 (C, C′, D, D′, G) and were then pulse-labeled with BrdU for 1 h before culling. RA treatments during E10.5–E11.5 result in increases of BrdU-positive cells (green nuclei) in the rostral, middle, and caudal levels of E11.5 wild-type LGE (B, B′, E), but not in RARβ−/− mutant LGE at the rostral and middle levels (F). The RA treatments during E12.5–E13.5 resulted in increases of BrdU-positive cells in the caudal (D, D′, G) but not the rostral and middle LGE (G). The bracketed regions in A, A′, C, C′ are shown at high magnification in B, B′, D, D′, respectively. *, P < 0.05; **, P < 0.01, ***, P < 0.001, Student's t test. All experiments were repeated at least three times. (Scale bars in A for A, A′, 200 μm; in B for B, B′, 100 μm; in C for C, C′, 200 μm; and in D for D, D′, 100 μm.)
Fig. 4.
Fig. 4.
Spatiotemporal regulation of endogenous RA in the LGE. None or at most few Raldh3-positive cells are present in E11.5 LGE (A). By E13.5, many Raldh3-positive cells are present in the rostral/middle part of LGE (B), but few Raldh3-positive cells are present in the caudal LGE (C). (D–I) Detection of endogenous RA in the LGE with the RA reporter cells assay. Few X-gal-positive Sil-15 reporter cells are present in the coculture of E11.5 LGE (D and G) or the caudal part of E13.5 LGE (F and I), whereas many X-gal-positive reporter cells are present in the coculture of rostral/middle part of E13.5 LGE (E and H). The bracketed regions in D–F are shown at high magnification in G–I, respectively. (Scale bars, in A–C, 200 μm; in D for D, E, 500 μm; in F, 500 μm; and in G for G–I, 50 μm.)
Fig. 5.
Fig. 5.
Behavioral analyses of RARβ−/− mutant mice. (A) The locomotor activity of RARβ−/− mutant mice does not differ from wild-type mice either with the challenges of vehicle or apomorphine (Apo, 3 mg/kg) at 20 and 50 min after drug injections. (B) Apomorphine significantly increases the head-bobbing movement in RARβ−/− mutant mice at 20 and 50 min after the drug injection compared with wild-type mice. Note that apomorphine at this low dose does not increase head bobbing in wild-type mice. (C) Apomorphine (3 mg/kg) completely inhibited the rearing activity of RARβ−/− mutant mice at 20 min after injection. ***, P < 0.001, two-way ANOVA, Bonferroni's post hoc test. Apo-20, Apo-50, Veh-20, Veh-50: 20 and 50 min after the injections of apomorphine or its vehicle.
Fig. 6.
Fig. 6.
Schematic drawings illustrating the working hypothesis of modular patterning of striatal compartments by RARβ signaling. The early-born S cells, because of deficiency of endogenous RA in the LGE during their neurogenesis at E10.5–E11.5, develop into a small S compartment in the caudal striatum. Subsequently elevated RA at E12.5–E13.5 enables full activation of RARβ signaling in late-born S cells, which leads to preferential expansion of the late-born S cell population. The expanded S cell population eventually evolves to form a large and elaborate S compartment in the rostral striatum, which may modulate psychomotor function. Note that, for simplicity, the effects of RA signaling on promoting differentiation of striatal neurons are omitted from the drawings.
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