Laura E. Martin

Neuregulins are ligands for the erbB family of receptor tyrosine kinases and mediate growth and differentiation of neural crest, muscle, breast cancer, and Schwann cells. Neuregulins contain an epidermal growth factor-like domain located C-terminally to either an Ig-like domain or a cysteine-rich domain specific to the sensory and motor neuron-derived isoform. Here it is shown that elimination of the Ig-like domain-containing neuregulins by homologous recombination results in embryonic lethality associated with a deficiency of ventricular myocardial trabeculation and impairment of cranial ganglion development. The erbB receptors are expressed in myocardial cells and presumably mediate the neuregulin signal originating from endocardial cells. The trigeminal ganglion is reduced in size and lacks projections toward the brain stem and mandible. We conclude that IgL-domain-containing neuregulins play a major role in cardiac and neuronal development.

Peripheral taste receptor cells use multiple signaling pathways to transduce taste stimuli into output signals that are sent to the brain. Transient receptor potential melastatin 5 (TRPM5), a sodium-selective TRP channel, functions as a common downstream component in sweet, bitter, and umami signaling pathways. In the absence of TRPM5, mice have a reduced, but not abolished, ability to detect stimuli, suggesting that a TRPM5-independent pathway also contributes to these signals. Here, we identify a critical role for the sodium-selective TRP channel TRPM4 in taste transduction. Using live cell imaging and behavioral studies in KO mice, we show that TRPM4 and TRPM5 are both involved in taste-evoked signaling. Loss of either channel significantly impairs taste, and loss of both channels completely abolishes the ability to detect bitter, sweet, or umami stimuli. Thus, both TRPM4 and TRPM5 are required for transduction of taste stimuli.

Mortality and cytokine production associated with disease models mediated by TNF- and IFN-gamma were studied in mice lacking IFN regulatory factor-1 (IRF-1). IRF-1 knockout (KO) mice showed no mortality after the injection of a dose of LPS lethal in intact control mice (LD95). KO mice showed lower circulating levels of TNF and IFN-gamma than controls. KO mice also showed lower TNF and IFN-gamma mRNA in the spleen or liver than controls. KO mice had smaller spleens than controls, which contained similar percentage but lower absolute count of macrophages and lower percentage and absolute count of NK cells. IRF-1 KO mice survived longer than controls after the coinjection of LPS and galactosamine. IRF-1 KO mice also showed less mortality than controls after the injection of Con A and in a model of cerebral malaria. After the injection of a lethal dose of TNF (LD88), mortality was similar between KO and intact mice. Mortality was also similar after the coinjection of two nonlethal doses of TNF and IFN-gamma, a lethal combination (LD100). This study shows that the lack of IRF-1 protects against the mortality associated with disease models mediated by TNF and IFN-gamma but has no effect on the mortality directly induced by TNF and IFN-gamma. The lack of IRF-1 appears to result in impaired production of TNF and IFN-gamma, reflecting a down-regulation of gene expression in the liver and spleen as well as a reduction in the number of splenic cells.