Ligand- and kinase activity-independent cell survival mediated by the epidermal growth factor receptor expressed in 32D cells.

To investigate the intrinsic activities of the epidermal growth factor receptor and the role of its kinase domain in these functions within a cellular environment lacking endogenous ErbB protein expression, wild-type EGF receptor (WT-EGFR) and two kinase-impaired mutants, D813A and K721R, were expressed in 32D murine hematopoietic cells, a line which is normally dependent on interleukin 3 (IL3) for growth and survival. Addition of EGF in the absence of IL3 stimulates receptor autophosphorylation and, in the presence of serum, mitosis in cells expressing WT-EGFR, but not in cells expressing D813A or K721R. Unexpectedly, cells expressing WT-EGFR or K721R exhibited IL3-independent survival in the presence of fetal bovine serum; parental 32D cells and cells expressing D813A did not survive, apparently undergoing apoptosis in the absence of IL3, whether or not serum was present. Addition of EGF did not prevent the apoptosis of WT-EGFR or K721R cells in serum-free medium. Activation of Akt was not necessary to mediate the prosurvival activity of EGF receptor expression. These results suggest that the EGF receptor can mediate the prevention of apoptosis independently of both receptor-ligand binding and receptor kinase activity, and this activity is disrupted by the D813A mutation.

A line of Berlin Druckrey IV rats proposed as a new model for human hereditary ataxia.

An experimental colony of Berlin Druckrey IV (BD IV) rats with inherited, congenital, gradually progressive incoordination and rear limb ataxia was evaluated for clinical signs, gross and microscopic nervous system lesions, and mode of inheritance of the gene defect. Clinical evaluation suggested a lesion in the midbrain or brainstem, with resulting lower motor neuron functional impairment. Gross alterations in affected rats were atrophy of thigh musculature by six months of age and thoracic kyphoscoliosis. Histological evaluation of the nervous system revealed central chromatolysis of neurons within the red nuclei in 20 out of 24 affected rats. Additionally, in six out of 24 affected rats chromatolytic neural cell bodies of this nucleus contained brightly eosinophilic, coarsely granular, cytoplasmic deposits. Special stains (osmium tetroxide, Kinyoun's acid-fast and periodic acid-Schiff) indicated these deposits consisted of lipopolysaccharide. Additional lesions in ataxic rats included qualitative reduction in neuronal cell bodies of the inferior olivary nucleus (10 out of 26 rats) and cerebellar Purkinje cells (5 out of 27 rats). No reduction in the number of spinal cord lower motor neurons was detected. Analysis of intercross pedigrees that were established between ataxic BD IV females and either normal Long Evans or Fisher males indicated a likely autosomal recessive mode of inheritance. The authors propose that this disease accompanying a new variant of the BD IV rat (to be designated "shaker" rat) provides a new and unique research model for ataxia with features in common with some human hereditary ataxias.