Nkx2-1 is a homeobox transcription factor that belongs to a large family of highly conserved proteins controlling the development of the ventral neural tube in vertebrates and invertebrates. In mammals, Nkx2-1 is one of the master regulators of basal forebrain development. It is expressed in progenitor cells in the ventral aspect of the telencephalon and in the hypothalamus, where it controls the specification of several neuronal populations (Sussel et al., 1999; Butt et al., 2008). In addition, Nkx2-1 has been shown to be expressed in some postmitotic neurons as they migrate away from their sources. Nkx2-1 regulates the expression of guidance receptors in these migrating cells, thereby controlling their final distribution (Nóbrega-Pereira et al., 2008). These results suggested that a classical cell fate regulator can be reused in migrating cells for a totally different function, i.e. cell migration.
In this issue of the European Journal of Neuroscience, Magno and colleagues describe a novel function for this industrious transcription factor. Prompted by the observation that Nkx2-1 expression is maintained by several neuronal populations in the adult basal forebrain (Marín et al., 2000; Magno et al., 2009), the authors studied the consequences of perinatal deletion of this gene. They found that Nkx2-1 is required for the survival of cholinergic neurons long after they have settled in the basal forebrain, thereby uncovering a novel role for this gene. Interestingly, the loss of cholinergic neurons after postnatal removal of Nkx2-1 is probably due to prolonged degeneration, similar to that found following axotomy or excitotoxic insults. This is in sharp contrast with the effects of the early postmitotic removal of Nkx2-1 in both GABAergic and cholinergic neurons, which the authors found to lead to an almost immediate cell death.
Let me consider briefly the clinical implications of this discovery. In humans, Nkx2-1 haploinsufficiency causes ‘brain–thyroid–lung’ syndrome, a disease that emerges postnatally within the first years of life and leads to childhood-onset chorea with hypothyroidism and pulmonary abnormalities (Kleiner-Fisman & Lang, 2007). Considering the function of Nkx2-1 in cell fate specification and migration, it has been speculated that the ‘brain–thyroid–lung’ syndrome might be caused by an early disruption in the development of the basal ganglia. However, this study now suggests that neuronal loss might also contribute to the defects observed in ‘brain–thyroid–lung’ syndrome. In addition, as loss of cholinergic neurons does not lead to major motor abnormalities, the study by Magno and colleagues also emphasizes the pivotal role that GABAergic neurons may have in the disorder.
In sum, the authors have published a well-designed, significant article that expands our knowledge on the diverse functions that the transcription factor Nkx2-1 plays during development. It remains to be elucidated how Nkx2-1 regulates cell integrity and survival. As suggested by the authors, Nkx2-1 may directly control the expression of receptors for neurotrophic factors, which are known to be essential for the survival of these cells (Smeyne et al., 1994). Further studies should explore this or alternative possibilities.