In the forebrain, although RA is not essential for generation of neural progenitor cells at early stages of development, it has been reported to be an important determinant of neuronal differentiation. The potential involvement of RA in development of midbrain dopaminergic neurons (mDA) was also suggested by RA-dependent prevention of stark deficits of mDA cell development in Pitx3−/− mice 15. At later phases of development, RA also contributes to the diversification of neuronal subtypes, as best illustrated for generation of motor neuron subtypes 8, 9, 10, 11 and formation of serotonergic 12, 13 and noradrenergic neurons 14. Notably, at early stages of development, RA instructs neuroectoderm differentiation towards neuronal progenitors and thus controls formation of generic neurons in future hindbrain and spinal cord 5, 6, 7. Research carried out over more than 30 years provided examples of critical roles of RA in generation of diverse neural cell types and neuronal subtypes in different regions of the nervous system (reviewed in ref. Retinoic acid (RA), the bioactive form of vitamin A, is essential for embryonic development by virtue of controlling proliferation, differentiation and homeostasis of diverse cell types, thus contributing to organogenesis and formation of different types of tissues including nervous tissue.
In contrast, activation of RARα is less efficient in generation of this class of neurons, but is essential for differentiation of functional dopaminergic neurons, which may correspond to a subpopulation of inhibitory dopaminergic neurons expressing glutamic acid decarboxylase in vivo.
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By using RARα, β and γ selective agonists we show that RARγ is the functionally dominant RAR in mediating RA control of early molecular determinants of MSNs leading to formation of striatopallidal-like neurons. Here we show that RA treatment during EC embryoid body formation is a highly robust protocol for generation of striatal-like GABAergic neurons which display molecular characteristics of striatopallidal medium spiny neurons (MSNs), including expression of functional dopamine D2 receptor. Although retinoic acid (RA) is a powerful inducer of neurogenesis in EC cells, it is not clear what specific neuronal subtypes are generated and whether different RAR isotypes may contribute to such neuronal diversification. Embryonal carcinoma (EC) cells are pluripotent stem cells extensively used for studies of cell differentiation.
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