Shh dependent and independent maintenance of basal midbrain

Abstract

Sonic hedgehog (Shh) is well known as the molecule responsible for the induction and maintenance of ventral neural tube structures. Recent data have shown that ventral neuronal populations react differentially to the amount of this morphogen not only in the spinal cord, but also in more rostral parts of the brain, like the midbrain. A dorsal expansion in the Shh expression domain modifies the differentiation program in this territory. The lack of Shh produces alterations in the development of this area as well. Here, for the first time, we analyze in detail the development of the different mesencephalic basal nuclei in the absence of Shh. We report that the oculomotor complex is lost, the dopaminergic populations are strongly affected but the red nucleus is maintained. These results point out that not all the midbrain neuronal populations are dependent on Shh for their maintenance, as previously thought. Based on our results and recently published data, we suggest the existence of a specific genetic pathway for the specification of the mesencephalic red nucleus. Foxa2 could be the candidate gene that might control this genetic pathway.

Foxa1 and Foxa2 positively and negatively regulate Shh signalling to specify ventral midbrain progenitor identity

“…Expression of Nkx6.1 in the ventral midbrain below the Nkx2.2+ regions was not affected in cyclopamine-treated control embryos, suggesting that Shh is also not required for this domain of expression from E9.5 onwards. This result is consistent with the observation that this domain of Nkx6.1 expression is still present in En1 cre/+ ; Shh flox/flox embryos, where Shh is inactivated by E9.0 (Perez-Balaguer et al, 2009).…”

The basic helix-loop-helix transcription factor Nato3 controls neurogenic activity in mesencephalic floor plate cells

“…S12 in the supplementary material). This is consistent with the previous observations that loss of Shh in mesFP cells did not affect but rather inhibited mesDA generation (Ferri et al, 2007;Perez-Balaguer et al, 2009). Thus, it is unlikely that upregulation of Shh is a major cause of the neurogenic defect in Nato3 mutants, although we could not rule out a possible involvement in part.…”

MicroRNAs

“…FoxA2 is also known to activate the expression of SHH in the VM (Bayly, Brown, & Agarwala, 2012). FoxA2 leads the neurogenic events by activating other transcriptional factors such as Nurr1 and Ngn2, and also promote the survival and maintenance of mDA, making FoxA2 a critical factor in orchestrating efficient mDA differentiation (Andersson, Irvin, Ahlsio, & Parmar, 2007;Perez-Balaguer, Puelles, Wurst, & Martinez, 2009). Of note, Ngn2 and Nurr1 gene expression is significantly reduced in HPRT-deficient neuron-like cells (Guibinga et al, 2010).…”