Targeted Disruption in the MouseHoxc-4Locus Results in Axial Skeleton Homeosis and Malformation of the Xiphoid Process

AbstractHoxc-4is a mouse homeobox gene located at the 3′ end of theHoxCcluster. Of theHoxCgenes,Hoxc-4is expressed in the most anterior regions of the central nervous system and prevertebral column. To investigate its role in mouse development, we have generatedHoxc-4mutant mice by gene targeting. Mice homozygous for theHoxc-4mutation are viable and fertile. Analysis of the skeletal system of homozygous mutants revealed various abnormalities in the cervical and thoracic regions. The most frequent abnormality was a partial posterior homeotic transformation of the seventh cervical vertebra. Less frequently, anterior transformations of the third and eighth thoracic vertebrae were observed. Furthermore, the xiphoid process of the sternum was malformed such that it had an aperture or a fissure. AlthoughHoxc-4is expressed abundantly in the central nervous system, no obvious defects were observed. These results suggest thatHoxc-4is required for specifying cervical and thoracic vertebral identity

Cav2.3 (α1E) Ca2+ channel participates in the control of sperm function

AbstractTo know the function of the Ca2+ channel containing α12.3 (α1E) subunit (Cav2.3 channel) in spermatozoa, we analyzed Ca2+ transients and sperm motility using a mouse strain lacking Cav2.3 channel. The averaged rising rates of Ca2+ transients induced by α-D-mannose–bovine serum albumin in the head region of Cav2.3−/− sperm were significantly lower than those of Cav2.3+/+ sperm. A computer-assisted sperm motility assay revealed that straight-line velocity and linearity were greater in Cav2.3−/− sperm than those in Cav2.3+/+ sperm. These results suggest that the Cav2.3 channel plays some roles in Ca2+ transients and the control of flagellar movement

Upregulation of casein kinase 1ε in dorsal root ganglia and spinal cord after mouse spinal nerve injury contributes to neuropathic pain

<p>Abstract</p> <p>Background</p> <p>Neuropathic pain is a complex chronic pain generated by damage to, or pathological changes in the somatosensory nervous system. Characteristic features of neuropathic pain are allodynia, hyperalgesia and spontaneous pain. Such abnormalities associated with neuropathic pain state remain to be a significant clinical problem. However, the neuronal mechanisms underlying the pathogenesis of neuropathic pain are complex and still poorly understood. Casein kinase 1 is a serine/threonine protein kinase and has been implicated in a wide range of signaling activities such as cell differentiation, proliferation, apoptosis, circadian rhythms and membrane transport. In mammals, the CK1 family consists of seven members (α, β, γ1, γ2, γ3, δ, and ε) with a highly conserved kinase domain and divergent amino- and carboxy-termini.</p> <p>Results</p> <p>Preliminary cDNA microarray analysis revealed that the expression of the <it>casein kinase 1 epsilon </it>(<it>CK1ε</it>) mRNA in the spinal cord of the neuropathic pain-resistant N- type Ca²⁺channel deficient (<it>Ca</it>_<it>v</it><it>2.2</it>^-/-) mice was decreased by the spinal nerve injury. The same injury exerted no effects on the expression of <it>CK1ε </it>mRNA in the wild-type mice. Western blot analysis of the spinal cord identified the downregulation of CK1ε protein in the injured <it>Ca</it>_<it>v</it><it>2.2</it>^-/-mice, which is consistent with the data of microarray analysis. However, the expression of CK1ε protein was found to be up-regulated in the spinal cord of injured wild-type mice. Immunocytochemical analysis revealed that the spinal nerve injury changed the expression profiles of CK1ε protein in the dorsal root ganglion (DRG) and the spinal cord neurons. Both the percentage of CK1ε-positive neurons and the expression level of CK1ε protein were increased in DRG and the spinal cord of the neuropathic mice. These changes were reversed in the spinal cord of the injured <it>Ca</it>_<it>v</it><it>2.2</it>^-/-mice. Furthermore, intrathecal administration of a CK1 inhibitor IC261 produced marked anti-allodynic and anti-hyperalgesic effects on the neuropathic mice. In addition, primary afferent fiber-evoked spinal excitatory responses in the neuropathic mice were reduced by IC261.</p> <p>Conclusions</p> <p>These results suggest that CK1ε plays important physiological roles in neuropathic pain signaling. Therefore CK1ε is a useful target for analgesic drug development.</p

Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca(2+) channel

The importance of voltage-dependent Ca(2+) channels (VDCCs) in pain transmission has been noticed gradually, as several VDCC blockers have been shown to be effective in inhibiting this process. In particular, the N-type VDCC has attracted attention, because inhibitors of this channel are effective in various aspects of pain-related phenomena. To understand the genuine contribution of the N-type VDCC to the pain transmission system, we generated mice deficient in this channel by gene targeting. We report here that mice lacking N-type VDCCs show suppressed responses to a painful stimulus that induces inflammation and show markedly reduced symptoms of neuropathic pain, which is caused by nerve injury and is known to be difficult to treat by currently available therapeutic methods. This finding clearly demonstrates that the N-type VDCC is essential for development of neuropathic pain and, therefore, controlling the activity of this channel can be of great importance for the management of neuropathic pain