Abstract
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.
Highlights
PACT and its murine ortholog RAX were originally identified as a protein activator for the double strand RNA (dsRNA)-dependent, interferon-inducible protein kinase PKR
High expression of RAX was observed in the cerebellum from postnatal day (PD) 4 to PD9, a period when the cerebellar granule neurons (CGNs) migrate from the external granule layer (EGL) to the internal granule layer (IGL)
The immunohistochemical (IHC) staining showed that RAX was highly expressed in EGL and Purkinje cell layer (PL) on PD4 and PD9 (Figure 1C), but the RAX-positive cells were only observed in Purkinje cells and interneurons in the internal granule layer (IGL) and molecular layer (ML) at PD15, PD21 and adulthood (Figure 1C)
Summary
PACT and its murine ortholog RAX were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase PKR. A transposon insertion in the 59-UTR of dRax (independently identified as loqs/R3D1) induces a highly abnormal commissural axon structure of the central nervous system (CNS) and 70% of the flies homozygous for the mutant allele die prior to adulthood[17] All these findings suggest that PACT/RAX plays an important role in embryogenesis and development. The third conserved motif of PACT/RAX is www.nature.com/scientificreports required for its role in migration which is independent of PKR and may be mediated by its interaction with FAK. These results reveal a novel role of PACT/RAX in regulating neuronal migration during the development
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