The protein kinase A regulatory subunit R1A (Prkar1a) plays critical roles in peripheral nerve development.
Signaling through cAMP has been implicated in Schwann cell (SC) proliferation and myelination, but the signaling pathway components downstream of cAMP required for SC function remain unknown. Protein kinase A (PKA) is a potential downstream effector of cAMP. Here, we induced loss of Prkar1a, the gene encoding the type 1A regulatory subunit of PKA, in SC to study its role in nerve development; loss of Prkar1a is predicted to elevate PKA activity. Conditional Prkar1a knock-out in mouse SC (Prkar1a-SCKO) resulted in a dramatic and persistent axonal sorting defect, and unexpectedly decreased SC proliferation in Prkar1a-SCKO nerves in vivo. Effects were cell autonomous as they were recapitulated in vitro in Prkar1a-SCKO SC, which showed elevated PKA activity. In the few SCs sorted into 1:1 relationships with axons in vivo, SC myelination was premature in Prkar1a-SCKO nerves, correlating with global increase in the cAMP-regulated transcription factor Oct-6 and expression of myelin basic protein. These data reveal a previously unknown role of PKA in axon sorting, an unexpected inhibitory role of PKA on SC cell proliferation in vivo and define the importance of Prkar1a in peripheral nerve development.
Division of Experimental Hematology and Cancer Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, Department of Molecular, Virology, Immunology, and Medical Genetics, and Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine The Ohio State University, Columbus, Ohio 43210.
Li
L
Guo
Audrey A
AA
Lee
Tilat A
TA
Rizvi
Nancy
N
Ratner
Lawrence S
LS
Kirschner
D000818:Animals; D002478:Cells, Cultured; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D005260:Female; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010525:Peripheral Nerves / Q000196:embryology* / Q000254:growth & development*; D011247:Pregnancy
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517835:Prkar1a protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases