title: Transgenic mice ectopically expressing HOXA5 in the dorsal spinal cord show structural defects of the cervical spinal cord along with sensory and motor defects of the forelimb.
abstract: Mutation of murine Hoxa5 has shown that HOXA5 controls lung, gastrointestinal tract and vertebrae development. Hoxa5 is also expressed in the spinal cord, yet no central nervous system phenotype has been described in Hoxa5 knockouts. To identify the role of Hoxa5 in spinal cord development, we developed transgenic mice that express HOXA5 in the dorsal spinal cord in the brachial region. Using HOXA5-specific antibodies, we show this expression pattern is ectopic as the endogenous protein is expressed only in the ventral spinal cord at this anterio-posterior level. This transgenic line (Hoxa5SV2) also displays forelimb-specific motor and sensory defects. Hoxa5SV2 transgenic mice cannot support their body weight in a forelimb hang, and forelimb strength is decreased. However, Rotarod performance was not impaired in Hoxa5SV2 mice. Hoxa5SV2 mice also show a delayed forelimb response to noxious heat, although hindlimb response time was normal. Administration of an analgesic significantly reduced the hang test defect and decreased the transgene effect on forelimb strength, indicating that pain pathways may be affected. The morphology of transgenic cervical (but not lumbar) spinal cord is highly aberrant. Nissl staining indicates superficial laminae of the dorsal horn are severely disrupted. The distribution of cells and axons immunoreactive for substance P, neurokinin-B, and their primary receptors were aberrant only in transgenic cervical spinal cord. Further, we see increased levels of apoptosis in transgenic spinal cord at embryonic day 13.5. Our evidence suggests apoptosis due to HOXA5 misexpression is a major cause of loss of superficial lamina cells in Hoxa5SV2 mice.
authors.affiliation: Interdepartmental Genetics, Iowa State University, Ames, IA 50011, USA.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Krieger
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Abbott
authors.forename: Milan
authors.initials: M
authors.lastname: Joksimovic
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lueth
authors.forename: Ioana M
authors.initials: IM
authors.lastname: Sonea
authors.forename: Lucie
authors.initials: L
authors.lastname: Jeannotte
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Tuggle
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002077:Butorphanol / Q000494:pharmacology / Q000627:therapeutic use; D002452:Cell Count / Q000379:methods; D003001:Cloning, Molecular / Q000379:methods; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D005552:Forelimb / Q000294:innervation / Q000473:pathology / Q000503:physiopathology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009294:Narcotics / Q000627:therapeutic use; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D015287:Neurokinin B / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D011930:Reaction Time / Q000235:genetics; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012678:Sensation Disorders / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology*; D013373:Substance P / Q000378:metabolism; D014157:Transcription Factors
chemical_list: C489213:HOXA5 protein, human; D018398:Homeodomain Proteins; C059637:Hoxa5 protein, mouse; D009294:Narcotics; D010750:Phosphoproteins; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D018042:Receptors, Neurokinin-3; D014157:Transcription Factors; D013373:Substance P; D015287:Neurokinin B; D002077:Butorphanol