PACT and its murine ortholog RAX were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase PKR. Recent studies indicated that RAX played a role in embryogenesis and neuronal development. In this study, we investigated the expression of RAX during the postnatal development of the mouse cerebellum and its role in the migration of cerebellar granule neurons (CGNs). High expression of RAX was observed in the cerebellum from postnatal day (PD) 4 to PD9, a period when the CGNs migrate from the external granule layer (EGL) to the internal granule layer (IGL). The migration of the EGL progenitor cells in vivo was inhibited by RAX knockdown on PD4. This finding was confirmed by in vitro studies showing that RAX knockdown impaired the migration of CGNs in cerebellar microexplants. PACT/RAX-regulated migration required its third motif and was independent of PKR. PACT/RAX interacted with focal adhesion kinase (FAK) and PACT/RAX knockdown disturbed the FAK phosphorylation in CGNs. These findings demonstrated a novel function of PACT/RAX in the regulation of neuronal migration.
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This research was supported by grants from the Ministry of Science and Technology of China (2010CB912000), the National Natural Science Foundation of China (31271142), the Program of Clinical Research Center, Institute for Nutritional Sciences and Xuhui Central Hospital (CRC20100010). Dr. J. Luo was supported by a grant from NIH/NIAAA (AA015407).
Yong, Yue; Meng, Ya; Ding, Hanqing; Fan, Zhiqin; Tang, Yifen; Zhou, Chenghua; Luo, Jia; and Ke, Zun-Ji, "PACT/RAX Regulates the Migration of Cerebellar Granule Neurons in the Developing Cerebellum" (2015). Pharmacology and Nutritional Sciences Faculty Publications. 29.
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Figure 1: RAX expression in developing mouse cerebellum.
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Figure 2: Effect of RAX knockdown on the migration of cerebellar granule neurons (CGNs).
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Figure 3: Effect of RAX knockdown on Bergman glia morphology and CGNs proliferation/differentiation.
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Figure 4: Effect of RAX knockdown on CGN migration in cerebellar microexplants.
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Figure 5: The third motif of RAX was required for the migration of CGNs in the developing cerebellum.
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Figure 6: RAX knockdown inhibited CGN migration independent of PKR in vivo.
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Figure 7: Interaction between PACT/RAX and FAK.