Disruption of the midkine gene (Mdk) delays degeneration and regeneration in injured peripheral nerve

Abstract

Midkine (MK) is a growth factor implicated in the development and repair of various tissues, especially neural tissues. MK acts as a reparative neurotrophic factor in damaged peripheral nerves. A postulated role of MK in the degeneration and regeneration of sciatic nerves was explored by comparing wild-type (Mdk(+/+)) mice with MK-deficient (Mdk(-/-)) mice after freezing injury. In the Mdk(-/-) mice, a regenerative delay was observed, preceded by a decelerated Wallerian degeneration (WD). The relative wet weight of the soleus muscle slowly declined, and recovery was delayed compared with that in the Mdk(+/+) mice. In the regenerating nerve, unmyelinated axons were unevenly distributed, and some axons contained myelin-like, concentrically lamellated bodies. In the endplates of soleus muscles, nerve terminals containing synaptic vesicles disappeared in both mice. In Mdk(-/-) mice, the appearance of nerve terminals was delayed in synaptic vesicles of terminal buttons after injury. The recovery of evoked electromyogram was delayed in Mdk(-/-) mice compared with Mdk(+/+) mice. Our results suggested a delay in axonal degeneration and regeneration in Mdk(-/-) mice compared with Mdk(+/+) mice, and the delayed regeneration was associated with a delayed recovery of motor function. These findings show that a lack of MK following peripheral nerve injury is a critical factor in degeneration and regeneration, and manipulation of the supply of MK may offer interesting therapeutic options for the treatment of peripheral nerve damage.

The Drosophila Midkine/Pleiotrophin Homologues Miple1 and Miple2 Affect Adult Lifespan but Are Dispensable for Alk Signaling during Embryonic Gut Formation

“…This is in agreement with the expression observed in larval tissues. The strong miple1 mRNA expression suggests a role for Miple1 in re- or degeneration of neurons, something that has been reported for both PTN [73] [74] [75] and MDK [76] [77].…”

Cortical gene expression in spinal cord injury and repair: insight into the functional complexity of the neural regeneration program

“…For example, within the first week of AST we could demonstrate an early and sustained upregulation of hand2 , encoding a bHLH transcription factor with crucial functions in neurogenesis and survival of sympathetic neurons as well as in neuronal differentiation (Doxakis et al, 2008; Schmidt et al, 2009). Interestingly, midkine ( mdk ) encoding a heparin-binding factor promoting growth, survival and/or migration of various target cells (Michikawa et al, 1993; Owada et al, 1999; Zou et al, 2006) and a critical factor in regeneration of injured peripheral nerves (Sakakima et al, 2009) showed a biphasic AST-induced expression pattern with significant upregulation starting at 7dpo. The ID HLH proteins act as transcriptional regulators during development and are generally considered as modulators of differentiation (Stewart et al, 1997; Norton et al, 1998).…”

“…It has been reported that Mdk promotes peripheral nerve regeneration (Sakakima et al, 2009), protects from focal brain ischemia and augments central neurogenesis (Ishikawa et al, 2009). Therefore, the long-lasting AST-triggered induction of mdk (7–60 dpo) as observed here may indicate a critical role of mdk in AST-induced neuroprotection and subsequent regeneration.…”

The midkine family of growth factors: diverse roles in nervous system formation and maintenance

“…Experimentally induced overexpression of Mdk and Ptn also showed neuroprotective effects in various mouse models for Parkinson's disease and Alzheimer's disease (see Muramatsu, ). Conversely, a Mdk deficiency results in a delay of neural degeneration and regeneration of the PNS (Sakakima et al ., ). Injury imposed on the peripheral sciatic nerve in wild‐type and Mdk ‐/‐ mice revealed a significant delay in nerve regeneration and recovery of the associated soleus muscle when Mdk was absent (Sakakima et al ., ).…”