Sox11 transcription factor modulates peripheral nerve regeneration in adult mice.
The ability of adult peripheral sensory neurons to undergo functional and anatomical recovery following nerve injury is due in part to successful activation of transcriptional regulatory pathways. Previous in vitro evidence had suggested that the transcription factor Sox11, a HMG-domain containing protein that is highly expressed in developing sensory neurons, is an important component of this regenerative transcriptional control program. To further test the role of Sox11 in an in vivo system, we developed a new approach to specifically target small interfering RNAs (siRNAs) conjugated to the membrane permeable molecule Penetratin to injured sensory afferents. Injection of Sox11 siRNAs into the mouse saphenous nerve caused a transient knockdown of Sox11 mRNA that transiently inhibited in vivo regeneration. Electron microscopic level analysis of Sox11 RNAi-injected nerves showed that regeneration of myelinated and unmyelinated axons was inhibited. Nearly all neurons in ganglia of crushed nerves that were Sox11 immunopositive showed colabeling for the stress and injury-associated activating transcription factor 3 (ATF3). In addition, treatment with Sox11 siRNAs in vitro and in vivo caused a transcriptional and translational level reduction in ATF3 expression. These anatomical and expression data support an intrinsic role for Sox11 in events that underlie successful regeneration following peripheral nerve injury.
Jankowski
Michael P
MP
Department of Neurobiology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
McIlwrath
Sabrina L
SL
Jing
Xiaotang
X
Cornuet
Pamela K
PK
Salerno
Kathleen M
KM
Koerber
H Richard
HR
Albers
Kathryn M
KM
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D057846:Cell-Penetrating Peptides; D002478:Cells, Cultured; D015536:Down-Regulation; D005727:Ganglia, Spinal / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009416:Nerve Regeneration; D010525:Peripheral Nerves / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000648:ultrastructure
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D055751:SOXC Transcription Factors; C490793:Sox11 protein, mouse; C414409:penetratin