ISDN2012_0186: A combinatorial in silico approach to model the glycosylated nornicotine‐curcumin paradigm in neuroprotection and neurotherapy for Alzheimer's disease

stages, it regulates different aspects of MN subtype identity. We previously showed that the transcriptional activators of the Onecut (OC) family (Hnf6/Oc1, Oc2 and Oc3) are expressed during MN differentiation. Here, we present evidence that the OC proteins regulate Isl1 expression and control distinct steps of MN development. First, we show that OC factors directly bind to the CREST2 enhancer of Isl1 and are necessary to maintain Isl1 expression in the early-born MN and in several MN subtype. Subsequently, the lack of OC and Isl1 alters the development of different MN subtype. Indeed, in the absence of OC factors, the ratio between somatic and visceral MN was modified and visceral MN were overproduced at the expense of somatic MN. Furthermore, specific aspects of visceral MN differentiation were affected. We also identified the transcriptional repressor Sip1 (Smad-Interacting Protein 1) as a novel regulator of visceral MN development. We propose a model wherein the OC proteins regulate a genetic network that control the differentiation balance between somatic and visceral MN. At limb levels, the identity of the medial part of the lateral motor column was lost and these MN acquired the molecular identity of the lateral population. Accordingly, ventral limb innervation was lost. Finally, the transitions between brachial, thoracic and lumbar MN columns, as well as the dorso-ventral extent of the lateral motor column, were altered in OC mutant embryos, suggesting that OC factors contribute to define the boundaries of the MN columns. Taken together, these observations indicate that OC factors regulate genetic networks that control neuronal identity and distribution at distinct steps of MN development.