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The Onecut (OC) family of transcription factors comprises three members in mammals, namely HNF-6 (or OC-1), OC-2 and OC-3. During embryonic development, these transcriptional activators control cell differentiation in pancreas, in liver and in the nervous system. In particular, they are collectively required for proper differentiation of the spinal motor neurons. The Hnf6-/- newborn mice suffer from paralysis of the hindlimbs. However, some of these animals show with age a progressive recovery of locomotor capacities. The goal of this project is to identify the causes of paralysis and mechanisms that are activated during locomotor recovery in Hnf6-/- mice. Spinal motor neurons were identified by immunofluorescence for motor neuron markers (Isl1, Hb9, VAChT) or by retrograde FluoroGold labeling. Neuromuscular junctions (NMJ) were visualized after alpha-bungarotoxin labeling and immunofluorescence for synaptophysin and neurofilaments on hindlimb muscle sections. Locomotor recovery was quantified by four complementary tests (neurological score, Grip Strength system, open field videotracking and catwalk analyses). In Hnf6-/- newborns, the amount of motor neurons was normal, suggesting that altered generation of motor neurons is not the cause of the paralysis. In contrast, the amount of astrocytes was reduced, indicating that the roles of HNF-6 during spinal cord development extend to astroglial differentiation. Interestingly, the morphology of the NMJ was severely altered in the absence of HNF-6, resulting in a ±40% reduction in hindlimb muscular strength. Preliminary observations suggested that locomotor improvement characterized by a partial recovery of muscle strength was initiated in some Hnf6-/- mice around 5-6 months of age. Current investigations aim to identify how HNF-6 controls NMJ formation and whether locomotor recovery correlates with any improvement in neuromuscular connections and/or with changes in the neuronal or glial compartments in the spinal cord
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Audouard, E., Schakman, O., Gailly, P., & Clotman, F. (2010). Locomotor deficit and recovery in Hnf6 knockout mice. E. Audouard, O. Schakman,. 7th Forum of European Neuroscience, Amsterdam, The Netherland. https://hdl.handle.net/2078.5/63632