Nature over nurture(Commentary on Rolando et al.)

The acquisition of mature neuronal phenotypes by progenitors residing in different germinal sites along the neuraxis is thought to be regulated by the expression of region-specific combinations of transcription factors or proneural genes. Nevertheless, heterotopic transplantation experiments suggest that fate choices of uncommitted cells can be changed after exposure to a novel neurogenic environment. However, whether progenitors taken from one region of the CNS can switch their fate to acquire features typical of a foreign site has remained controversial. This issue has been recently addressed by James Goldman’s group, by transplanting progenitors isolated from the forebrain subventricular zone to the prospective white matter (PWM) of the postnatal cerebellum (Milosevic et al., 2008). As shown by the same group several years ago (Zhang & Goldman, 1996), the PWM is the germinal site where the different types of inhibitory cerebellar interneurons are generated. The transplanted forebrain cells failed to activate regulatory genes specific of cerebellar interneurons, such as Pax-2 (Maricich & Herrup, 1999). Nonetheless, they engrafted in the cerebellum and developed mature neurons, which were assigned to different categories of local interneurons, based on their morphology and localization. Hence, it was concluded that extracerebellar donors differentiate into cerebellar-like interneurons. In the article published in this issue of EJN, Rolando et al. (2010) compared the developmental potentialities of progenitors from different sites along the neuraxis exposed to the postnatal cerebellar PWM. To identify the phenotypes acquired by donor cells, these investigators applied a set of concurrent criteria, including expression of region-specific transcription factors, morphological features, neurochemical profiles and position in the recipient architecture. Most importantly, starting from the recent work of Fernando Rossi and collaborators, showing that the phenotype and position of cerebellar interneurons are specified according to precise spatio-temporal patterns (Jankovski et al., 1996; Carletti et al., 2002; Leto et al., 2006, 2009), Rolando et al. (2010) asked whether extracerebellar donors shared the same developmental phases and final fate of the cerebellar interneurons generated at the age when transplantation was done. Although the results of these experiments are partly consistent with those of Milosevic et al. (2008), the conclusions are quite different. The morphology, position and expression of type-specific markers in donor neurons did not correspond to those of their age-matched cerebellar counterparts. Furthermore, the morphological features of donor neurons that may be termed ‘cerebellar-like’ appeared to result from local interactions at the homing site rather than from the unfolding of a host-specific ontogenetic program. Interestingly, the acquisition of such features occurs more frequently when donor cells are derived from sites close to the cerebellum along the rostro-caudal extent of the neuraxis. Thus, although exogenous neurons stably engraft in the cerebellum and acquire some features reminiscent of local interneurons, it is clear that they develop according to their own native properties and fail to become integrated into the host ontogenetic mechanisms. Thus, the results reported by Rolando et al. (2010) indicate that changing the regional identity of neural progenitors is not an easy task.