Regulation of spinal motoneuron differentiation by the combined action of sonic hedgehog and and neurotrophin 3

1, The development of ventral cell types in the spinal cord, including moto r neurons, requires the growth factor Sonic hedgehog (Shh), However, it is still unknown whether Shh acts directly on precursors to induce these cell types and whether additional factors are required for induction. 2, To further investigate the precise role of Shh in spinal motoneuron deve lopment, we used low-density cultures of murine spinal cord precursor cells , 3, Although purified Shh stimulated neuronal differentiation, it did not in crease the proportion of neurons expressing the motoneuron marker Islet-1 ( Isl-1), In contrast, purified Shh induced Isl-l expression in neural tube e xplants, suggesting that additional neural tube-derived factors are require d to induce motoneuron differentiation. 4, A factor implicated in motoneuron development, neurotrophin 3 (NT3), had no effect on Isl-1 expression; however in combination with Shh, it induced Isl-1 expression in the majority of neurons in the low-density cultures. F urthermore, in explant cultures, Shh-induced Isl-1 expression was blocked b y an anti-NT3 antibody, 5, In addition, previous studies have shown expression of NT3 in the region of motoneuron differentiation and the loss of spinal fusimotor neurons in NT3-knockout animals. 6, Taken together, these findings suggest that Shh can act directly on spin al cord precursors to promote neuronal differentiation, but induction of Is l-1 expression and motor differentiation requires additional factors, inclu ding NT3.