| Type of Document |
Dissertation |
| Author |
Jankowski, Michael Paul
|
| Author's Email Address |
mpjst5@pitt.edu |
| URN |
etd-10302006-082955 |
| Title |
NEURON SURVIVAL, AXON GROWTH AND THE
TRANSCRIPTION FACTOR SRY-BOX CONTAINING GENE 11 (SOX11) |
| Degree |
Doctor of Philosophy |
| Program |
Neurobiology |
| School |
School of Medicine |
| Advisory Committee |
| Advisor Name |
Title |
| Brian M. Davis, PhD |
Committee Chair |
| Cynthia Lance-Jones, PhD |
Committee Member |
| H. Richard Koerber, PhD |
Committee Member |
| Qiufu Ma, PhD |
Committee Member |
| Susan R. Sesack, PhD |
Committee Member |
|
| Keywords |
- neurite growth
- nerve regeneration
- neuron survival
- siRNA
- sox genes
- transcription factor
|
| Date of Defense |
2006-10-11 |
| Availability |
unrestricted |
Abstract
Developmental survival, axon growth and differentiation of sensory neurons are mediated through the actions of specific sets of transcriptional signaling complexes (Anderson, 1999). A newly recognized family of transcription factors that appear to have important roles in sensory neuron biology is the Sox family of high-mobility group (HMG) domain proteins. In a screen of transcriptional activity in transgenic animals that overexpress either NGF or GDNF in the skin (NGF-OE and GDNF-OE mice), the transcription factor Sox11 was significantly increased in developing neurons of the trigeminal ganglia. This increase suggests Sox11 expression is trophic factor sensitive and that it may contribute to the transcriptional control of genes involved in the increased survival and axonal projections that has been documented in these transgenic animals (Albers et al., 1994; Zwick et al., 2002). Sox11 was also increased in neurons of adult dorsal root ganglia (DRG) following sciatic nerve cut. The rise in Sox11 in response to enhanced trophic factor level and axotomy has led us to hypothesize that Sox11 is an essential transcriptional regulator in both embryonic and adult systems that is trophic factor responsive.
To further investigate the role of Sox11 and begin to identify transcriptional targets, the level of Sox11 was assayed in the Neuro2A stem cell line (Klebe and Ruddle, 1969), primary dorsal root ganglion (DRG) neurons and in vivo after nerve injury. Upon retinoic acid (RA)- induced differentiation of Neuro-2A cells and upon culturing DRG neurons, Sox11 mRNA increased, suggesting Sox11 was important for expression of genes involved in Neuro2A and primary DRG differentiation and survival. To test this, the level of Sox11 expression was knocked down in Neuro2A cells and cultured DRG neurons by transfection of siRNAs against Sox11. Knockdown of Sox11 in these cells caused cell death and inhibited axon growth. RNAi knockdown of Sox11 in vivo after a saphenous nerve crush injury also inhibited axon regeneration. These data suggest that the developmentally regulated transcription factor Sox11 is induced in adult neurons after injury to promote neurite growth and axon regeneration and inhibit apoptosis by regulating genes associated with each of these distinct biological pathways.
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56K Modem |
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JankowskiMP2006.pdf |
4.26 Mb |
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