A. Munoz et al., THYROID-HORMONE RECEPTOR C-ERBA - CONTROL OF COMMITMENT AND DIFFERENTIATION IN THE NEURONAL CHROMAFFIN PROGENITOR LINE-PC12, The Journal of cell biology, 121(2), 1993, pp. 423-438
The c-erbA proto-oncogenes encode nuclear receptors for thyroid hormon
e (T3), a hormone intimately involved in mammalian brain maturation. T
o study thyroid hormone receptor (TR) action on neuronal cells in vitr
o, we expressed the chicken c-erbA/TRalpha-1 as well as its oncogenic
variant v-erbA in the adrenal medulla progenitor cell line PC12. In th
e absence of T3, exogenous TRalpha-1 inhibits NGF-induced neuronal dif
ferentiation and represses neuron-specific gene expression. In contras
t, TRalpha-1 allows normal differentiation and neuronal gene expressio
n to occur in the presence of T3. Finally, TRalpha-1-expressing cells
become NGF-responsive for proliferation when T3 is absent, but NGF-dep
endent for survival in presence of T3. A similar differentiation induc
tion by NGF plus T3 was observed in a central nervous system-derived n
euronal cell line (E 18) expressing exogenous TRalpha-1. Together with
the finding that TRalpha-1 constitutively blocked dexamethasone-induc
ed differentiation of PC12 cells into the chromaffin pathway, these re
sults suggest that TRalpha-1 plays an important role in regulating com
mitment and maturation of neuronal progenitors. In contrast, the v-erb
A oncogene, a mutated, oncogenic version of TRalpha-1, partially but c
onstitutively inhibited NGF-induced neuronal differentiation of PC12 c
ells and potentiated dexamethasone-induced chromaffin differentiation,
giving rise to an aberrant ''interlineage'' cell phenotype.