Abstract
Here, we found that the PR domain protein Prdm8 serves as a key regulator of the length of the multipolar phase by controlling the timing of morphological transition. We used a mouse line with expression of Prdm8-mVenus reporter and found that Prdm8 is predominantly expressed in the middle and upper intermediate zone during both the late and terminal multipolar phases. Prdm8 expression was almost coincident with Unc5D expression, a marker for the late multipolar phase, although the expression of Unc5D was found to be gradually down-regulated to the point at which mVenus expression was gradually up-regulated. This expression pattern suggests the possible involvement of Prdm8 in the control of the late and terminal multipolar phases, which controls the timing for morphological transition. To test this hypothesis, we performed gain- and loss-of-function analysis of neocortical development by using in utero electroporation. We found that the knockdown of Prdm8 results in premature change from multipolar to bipolar morphology, whereas the overexpression of Prdm8 maintained the multipolar morphology. Additionally, the postnatal analysis showed that the Prdm8 knockdown stimulated the number of early born neurons, and differentiated neurons located more deeply in the neocortex, however, majority of those cells could not acquire molecular features consistent with laminar location. Furthermore, we found the candidate genes that were predominantly utilized in both the late and terminal multipolar phases, and these candidate genes included those encoding for guidance molecules. In addition, we also found that the expression level of these guidance molecules was inhibited by the introduction of the Prdm8 expression vector. These results indicate that the Prdm8-mediated regulation of morphological changes that normally occur during the late and terminal multipolar phases plays an important role in neocortical development.
Highlights
Most neocortical projection neurons originate from the asymmetric division of the radial glia progenitors in the ventricular zone (VZ) [1]
Prdm8 is expressed in the MP phase at embryonic stages In the P19 embryonal carcinoma cell line, we found a gradual increase in the Prdm8 mRNA level with neural differentiation after the treatment with retinoic acid, and this increment was almost coincident with the expression of post-mitotic neuronal markers
Other studies, including our previous study [29,30] have shown that Prdm8 expression was restricted to post-mitotic cells from embryonic day 13 (E13) to E18 during neocortical development
Summary
Most neocortical projection neurons originate from the asymmetric division of the radial glia progenitors in the ventricular zone (VZ) [1]. The neurons generated in VZ move radially to the subventricular zone (SVZ) and lower-intermediate zone (IZ), where they assume a multipolar (MP) morphology (Figure 1K) [2,3]. They dynamically extend and retract multiple long projections, and move in apparently random directions towards both the lower-IZ and middle-IZ [4,5]. Neurons with BP cell morphology move by locomotion along the radially oriented glial processes to their appropriate location within the developing cortical plate (CP) [7]. Transcriptional factors such as Pax, Tbr, NeuroD1, and Tbr1 [8–12] and their gene regulatory networks play key roles to proceed cell state during neural migration from the VZ to the CP
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