PACAP decides neuronal laminar fate via PKA signaling in the developing cerebral cortex

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Abstract

Laminar formation in the developing cerebral cortex requires the precisely regulated generation of phenotype-specified neurons. To test the possible involvement of pituitary adenylate cyclase-activating polypeptide (PACAP) in this formation, we investigated the effects of PACAP administered into the telencephalic ventricular space of 13.5-day-old mouse embryos. PACAP partially inhibited the proliferation of cortical progenitors and altered the position and gene-expression profiles of newly generated neurons otherwise expected for layer IV to those of neurons for the deeper layers, V and VI, of the cerebral cortex. The former and latter effects were seen only when the parent progenitor cells were exposed to PACAP in the later and in earlier G1 phase, respectively; and these effects were suppressed by co-treatment with a protein kinase A (PKA) inhibitor. These observations suggest that PACAP participates in the processes forming the neuronal laminas in the developing cortex via the intracellular PKA pathway.

Section snippets

Materials and methods

Animals and surgery. Pregnant ddY mice were purchased from Japan SLC (Shizuoka, Japan), and handled according to the Guidelines of Experimental Animal Care issued by the Office of the Prime Minister of Japan. Surgery and manipulation of animals were performed as described [8], [11]. Briefly, pregnant mice carrying 13.5-day-old embryos (E13.5) were anesthetized with sodium pentobarbital (30 μg/g, i.p.), and their uterine horns were exposed. About 1 μl of phosphate-buffered saline (PBS) containing

Alteration of the position of cortical neurons by PACAP

We labeled the progenitors with BrdU 6 h after PACAP or vehicle administration on E13.5 and examined the distribution of the labeled cells at P6 with a confocal laser microscope (Fig. 1A). The greatest numbers of cellsBrdU+ were observed in sector nos. 6–7, corresponding to layer IV of the cerebral cortex, in the vehicle-injected animals (Fig. 1A,B). However, in the PACAP-treated animals, most of the cellsBrdU+ was localized in sector nos. 2–5, corresponding to layers V and VI (Fig. 1A,B). Thus

Discussion

In this study, we revealed that PACAP stimulated the phosphorylation of CREB of the embryonic cortical progenitors. We propose that phosphorylated CREB mediated the release of cortical progenitors from the cell cycle and altered the laminar fate of their daughter neurons, because both actions were completely blocked by PKA inhibitor co-administered with PACAP. Also, the PKA inhibitor behaved oppositely against PACAP actions on the cortical progenitors. Therefore, PKA/CREB signaling would be

Acknowledgment

This work was supported in part by grants from the programs Grants-in-Aid for Young Scientists (B; to H.F.) and Scientific Research (B; to S. F.) of the Japan Society for the Promotion of Science.

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