Abstract
Inactivation of the gene encoding the POU domain transcription factor BRN-3A results in the absence of specific neurons in knockout mice. Here we demonstrate for the first time a direct effect of BRN-3A on the survival of neuronal cells. Specifically, overexpression of BRN-3A in cultured trigeminal ganglion or dorsal root ganglion sensory neurons enhanced their survival following the withdrawal of nerve growth factor. Moreover, reduction of BRN-3A levels impaired the survival of these neurons. The survival of sympathetic neurons was not affected by either approach. Similarly, overexpression of BRN-3A activated the endogenous Bcl-2 gene in trigeminal neurons, but not in sympathetic neurons. The protective effect of BRN-3A on trigeminal neuron survival following nerve growth factor withdrawal significantly increased during embryonic development. In contrast, overexpression of the related factor BRN-3B enhanced survival of trigeminal neurons only at an early stage of embryonic development. Thus, BRN-3A (and in some circumstances, BRN-3B) can promote the survival of nerve growth factor-dependent sensory but not sympathetic neurons, allowing it to play a direct role in the survival of some (but not all) neuronal populations in the developing and adult nervous systems.
Highlights
The BRN-3 transcription factors are members of the POU family of transcription factors, which was originally defined on the basis of a common 150 –160-amino acid DNA-binding domain found in the mammalian transcription factors Pit-1, Oct-1, and Oct-2 and the nematode regulatory protein Unc-86
BRN-3A has previously been shown to be expressed at high levels in trigeminal ganglion neurons [7, 25], and significant losses of such neurons are observed in Brn-3a knockout mice, with the size of the ganglion at E20 being approximately half that in wild-type or heterozygous mice and the dorsal division of the anteromedial lobe of the ganglion being completely absent at postnatal day 0.5 [17, 18]
The BRN-3A POU family transcription factor clearly plays an essential role in the correct development of the nervous system, with significant losses of sensory and motor neurons being observed in knockout mice lacking a functional gene for this factor [17, 18]
Summary
The BRN-3 transcription factors are members of the POU family of transcription factors, which was originally defined on the basis of a common 150 –160-amino acid DNA-binding domain found in the mammalian transcription factors Pit-1, Oct-1, and Oct-2 and the nematode regulatory protein Unc-86 (for review, see Refs. 1 and 2). In contrast to the relatively organ-specific effects of inactivation of Brn-3b or Brn-3c, inactivation of BRN-3A causes widespread losses of specific populations of motor neurons and of proprioreceptive, mechanoreceptive, and nociceptive sensory neurons This results in mice with uncoordinated limb movement and impaired suckling that die shortly after birth [17, 18]. The losses of neuronal cells in Brn-3a knockout mice have previously been suggested to be due to a loss of expression of specific neurotrophic factors or their receptors [17] This would disrupt neurotrophin signaling, resulting in a loss of their survival-promoting effects and leading to the observed neuronal cell death. We have investigated the effect of increasing or decreasing the levels of BRN-3A in specific neuronal cell types on their survival in the presence or absence of neurotrophins
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