Mechanisms of reparative growth in adult peripheral cutaneous nerves

Abstract

<p>This thesis involved the use of mutant and transgenic mice to examine the role of<br />various factors in reparative growth of the adult peripheral nervous system. These animals<br />have genetic defects that could be anticipated to affect reparative growth of sensory nerves,<br />and included mice that are transgenic for the heavy chain neurofilament (NFH)lacZ fusion<br />construct, mice mutant either in the steel or the c-kit locus, and mice with a null mutation in<br />the gene coding for the low-affinity neurotrophin receptor (p75^NGFR).</p> <p>Both collateral sprouting and regeneration occurred in the NFHlacZ mice at a rate<br />similar to that observed in control mice. Therefore, overexpression of the NFHlacZ construct<br />had no effect on reparative growth of sensory nerves.</p> <p>Interestingly, regeneration of all three fibre types examined was impaired in mice<br />that have a mutation in the gene coding for Steel or c-Kit, and occured at a rate of 1/2 to 2/3<br />of that observed in control animals. However, the rate ofcollateral sprouting was normal.</p> <p>Although the sensory nerves of p75^NGFR mice underwent normal regeneration,<br />collateral sprouting was completely absent. Interestingly, exogenous NGF induced this form<br />of growth in these animals.</p> <p>In addition, there was a significant decrease in the number of axons comprising all three fibre types in the sensory nerves in both the SI/Sld, WIW and p75^NGFR mice,<br />suggesting that the molecules involved also play a role in the development of sensory<br />neurons.</p> <p>NGF-induced hyperalgesia was not evident in the control or knockout animals upon<br />exogenous administration of either 1 or 2.5μg/g of NGF. However, administration of<br />2.5μg/g of NGF resulted in a significant mechanical hyperalgesia in both the control and<br />knockout mice. Thus, it appears that the low-affinity neurotrophin receptor does not play a<br />role in NGF-induced hyperalgesia.</p>