An alternative retinoid pathway regulating vertebrate neurogenesis

We have identified a novel way to control whether cells in the developing nervous system continue to multiply or stop dividing and become nerve cells. Our preliminary experiments strongly suggest that this is directed by the expression of a gene called fatty acid binding protein 5 (Fabp5); when Fabp5 is over-expressed in the early nervous system cells keep dividing, while blocking its expression reduces cell proliferation. In skin cells, Fabp5 has been shown to promote cell division by binding retinoic acid and presenting this to a receptor that stimulates genes that increase cell proliferation and survival. Furthermore, levels of Fabp5 determine whether retinoic acid promotes or inhibits proliferation. We propose here to test whether Fabp5 works by a similar mechanism in vertebrate neural tissue and in embryonic stem (ES) cells. If this is the case, we may be able to use Fabp5 to coordinate and direct ES cell differentiation in culture dishes and so improve the production of neural tissue for replacement following neural damage or disease or for testing the effects of new drugs. Inhibiting Fabp5 might also increase the effectiveness of retinoic acid mediated differentiation therapy used to treat Neuroblastoma, an aggressive childhood cancer.

Generation of the nervous system is a fundamental process governed by the balance between proliferation and differentiation of neural progenitor cells. Retinoid signalling is well known to drive neuronal differentiation, however, it is also required for proliferation of neural tissue and the molecular mechanism that determines these distinct outcomes is unknown. Using a genome-wide screen we have identified Fatty Acid Binding Protein 5 (Fabp5) as a gene expressed in newly formed neural progenitors and recent findings in keratinocytes have shown that Fabp5 mediates an alternative retinoid pathway, which can promote proliferation. Our preliminary data shows that Fabp5 inhibits neuron production in the chick neural tube and is required for normal proliferation in this tissue supporting a similar function during the generation of vertebrate nervous system. We propose here to investigate the role, regulation and mechanism of action of Fabp5 using gain and loss of function approaches in chick and mouse neural tube and in ES cell derived neural progenitors.