Caspase 3 deficiency rescues peripheral nervous system defect in retinoblastoma nullizygous mice

The retinoblastoma tumor suppressor protein, pRb, is a key regulator of cel l cycle and has been implicated in the terminal differentiation of neuronal cells. Mice nullizygous for pRb die by embryonic day 14.5 from hematopoiet ic and neurological defects attributed to failed differentiation (Clarke et al., 1992; Jacks et al., 1992; Lee et al., 1992). Previous studies by MacL eod et al. (1996) have demonstrated that the loss of p53 protects Rb-defici ent CNS neurons but not peripheral nervous system (PNS) neurons from cell d eath. Thus, the mechanisms by which PNS neurons undergo apoptosis in respon se to Rb deficiency remain unknown. In view of the pivotal role of caspase 3 in the regulation of neuronal apoptosis during development, we examined i ts function in the execution of the wide-spread neuronal cell death induced by Rb deficiency. Our results support a number of conclusions. First, we s how that caspase 3 becomes activated in all neuronal populations undergoing apoptosis. Second, caspase 3 deficiency does not extend the life span of R b null embryos, because double null mutants exhibit high rates of liver apo ptosis resulting in erythropoietic failure. Third, Rb/caspase 3 double-muta nt neurons of the CNS exhibit widespread apoptosis similar to that seen in Rb mutants alone; thus caspase 3 deficiency does not protect this populatio n from apoptosis. Finally, in contrast to the CNS, neurons of the PNS inclu ding those comprising the trigeminal ganglia and the dorsal root ganglia ar e protected from apoptosis in Rb/caspase 3 double-mutant embryos. Examinati on of the mechanistic differences between these two cell types suggest that CNS neurons may invoke other caspases to facilitate apoptosis in the absen ce of caspase 3. These findings suggest that PNS neurons are dependent on c aspase 3 for the execution of apoptosis and that caspase 3 may serve as a k ey therapeutic target for neuroprotection after injury of this cell type.