Changes of signaling molecules in the axotomized rat facial nucleus

Abstract

Axotomy of the rat facial nerve causes downregulation of motoneuron-specific molecules, including choline acetyltransferase and the vesicular acetylcholine transporter, in surviving motoneurons. Subsequently, resident microglia are activated and proliferate. These cellular responses are thought to promote the survival, repair and regeneration of motoneurons. However, it is still unclear which signaling molecules are involved in these responses. In this study, we investigated the changes and localizations of several signaling molecules, including immediate early genes (IEGs) such as c-Jun and c-Fos, transcription factors such as cAMP responsive element binding protein (CREB) and activating transcription factor 2 (ATF2), and mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and p38. Immunoblotting and immunohistochemical analyses revealed the following. Among the IEGs, c-Jun was increased in injured motoneurons, but c-Fos did not respond to neuronal injury. Among the CREB/ATF family members, phosphorylated CREB (p-CREB) was significantly decreased in injured motoneurons. The levels of p-CREB/CREB and ATF2 were immunohistochemically increased in microglia. Among MAPKs, p-ERK1/2 and p-JNK1 were decreased in injured motoneurons at the late stage. p-p38 and p38 were markedly increased in microglia. In vitro experiments revealed that p38 and CREB were activated in proliferating microglia. These results strongly suggested that c-Jun is involved in the survival, repair and regeneration of motoneurons, but p-CREB/CREB, p-ERK/ERK and p-JNK/JNK are associated with the downregulation of motoneuron-specific molecules. On the other hand, p-p38/p38 and p-CREB/CREB were suggested to be closely involved in the activation/proliferation of microglia.

Mechanisms of Microglia Proliferation in a Rat Model of Facial Nerve Anatomy

“…In the facial nerve transection model using newborn rats, Graeber et al reported that the microglial cell number increased in the axotFN with a peak at 5-7 days post-injury [68]. On postnatal day 2 (p2d)-rats, the increased cell number in the axotFN reached a peak at 5-7 days post-insult [69] (Figure 2C, p2d). How does this time course compare to the case of senescent (aged) animals?…”