Functions and regulation of DUSP6 in Schwann cells and oligodendrocytes after injury

• Applicant: Professorin Dr. Claire Jacob
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 467386109

In case of a traumatic injury in the peripheral nervous system (PNS), Schwann cells, the myelinating glia of the PNS, demyelinate and convert into repair cells to promote axonal regrowth. In contrast, oligodendrocytes, the myelinating glia of the central nervous system (CNS), remain at their myelinating state or die after a CNS lesion and their myelin that contains growth-inhibitory factors prevents axonal regrowth. We found that DUSP6, a phosphatase that inhibits the activation of ERK1/2, is rapidly downregulated in Schwann cells after axonal lesion in culture and after a sciatic nerve crush injury in mice, whereas DUSP6 is rapidly upregulated in oligodendrocytes after axonal lesion in culture and after a spinal cord injury in mice. Consistently, ERK1/2 is rapidly activated in Schwann cells after a sciatic nerve injury, but not in oligodendrocytes after a spinal cord injury. By using lesion models that we have recently set up in microfluidic chambers, we found that downregulating DUSP6 in oligodendrocytes by shRNA promotes axonal regrowth. The aim of this project is to elucidate how DUSP6 downregulation in oligodendrocytes promotes axonal regrowth and whether DUSP6 downregulation in Schwann cells is necessary for axonal regrowth after lesion, identify the mechanisms that regulate DUSP6 expression in Schwann cells and oligodendrocytes after lesion, design exploratory treatments to downregulate DUSP6 in oligodendrocytes and test whether this promotes axonal regrowth after spinal cord injury in mouse models.

• DFG Programme: Research Grants