Sulfatase 1 Promotes the Motor Neuron-to-Oligodendrocyte Fate Switch by Activating Shh Signaling in Olig2 Progenitors of the Embryonic Ventral Spinal Cord

Abstract

In the developing ventral spinal cord, motor neurons (MNs) and oligodendrocyte precursor cells (OPCs) are sequentially generated from a common pool of neural progenitors included in the so-called pMN domain characterized by Olig2 expression. Here, we establish that the secreted Sulfatase 1 (Sulf1) is a major component of the mechanism that causes these progenitors to stop producing MNs and change their fate to generate OPCs. We show that specification of OPCs is severely affected in sulf1-deficient mouse embryos. This defect does not rely on abnormal patterning of the spinal cord or failure in maintenance of pMN progenitors at the onset of OPC specification. Instead, the efficiency of OPC induction is reduced, only few Olig2 progenitors are recruited to generate OPCs, meanwhile they continue to produce MNs beyond the normal timing of the neuroglial switch. Using the chicken embryo, we show that Sulf1 activity is required precisely at the stage of the MN-to-OPC fate switch. Finally, we bring arguments supporting the view that Sulf1 controls the level of Sonic Hedgehog (Shh) signaling activity, behaving as an enhancer rather than an obligatory component in the Shh pathway. Our study provides additional insights into the temporal control of Olig2 progenitor cell fate change by the identification of Sulf1 as an extracellular timing signal in the ventral spinal cord.

Dynamics of Sonic hedgehog signaling in the ventral spinal cord are controlled by intrinsic changes in source cells requiring Sulfatase 1

“…Strikingly, this neuroglial switch is also controlled by Shh, responsible at that time for a rearrangement of the ventral patterning, resulting in generation of the p* domain. This domain forms following dorsal expansion of Nkx2.2 expression in Olig2 progenitors in response to a rise in Shh signaling Danesin et al, 2006;Fu et al, 2002;Touahri et al, 2012;Zhou et al, 2001). At this stage, Nkx2.2 no longer represses Olig2 and their co-expression drives p* progenitors to the OPC fate.…”

“…At this stage, Nkx2.2 no longer represses Olig2 and their co-expression drives p* progenitors to the OPC fate. We identified the secreted enzyme Sulfatase1 (Sulf1) as a major player in triggering this cell fate change in amniotes (Touahri et al, 2012). By modulating the sulfation state of heparan sulphate proteoglycans (HSPGs) at the cell surface, Sulf1 regulates interaction of HSPGs with morphogen factors (Ai et al, 2003;Dhoot et al, 2001;Freeman et al, 2008;Lamanna et al, 2007;Meyers et al, 2013;Viviano et al, 2004;Wang et al, 2004).…”

“…In Drosophila, Sulf1 has opposing functions, enhancing Hh release from its source and reducing Hh signaling activity in the responding cells (Wojcinski et al, 2011). In vertebrate spinal cord, Sulf1 only behaves as a positive modulator of Shh signaling (Danesin et al, 2006;Touahri et al, 2012). Strikingly, the expression of Sulf1 is highly dynamic in this tissue.…”

“…Strikingly, the expression of Sulf1 is highly dynamic in this tissue. Its function in triggering the MN/OPC fate switch is related to its upregulation in Nkx2.2 progenitors (Braquart-Varnier et al, 2004;Danesin et al, 2006;Touahri et al, 2012), suggesting that Sulf1, by lowering the Shh-HSPG interaction at the surface of p3 progenitors, helps to provide higher doses of Shh, free to travel dorsally, to Olig2 progenitors. However, the mechanism by which Sulf1 non-cell autonomously activates Shh signaling has yet to be elucidated.…”

“…Before patterning rearrangement, Sulf1 is expressed in the ventral neural tube (Braquart-Varnier et al, 2004;Danesin et al, 2006;Gorsi et al, 2010;Meyers et al, 2013;Touahri et al, 2012), opening the possibility that it could also influence Shh signaling at stages of patterning establishment. We report that, in addition to its function in stimulating OPC induction, Sulf1 activity is crucial for generation of ventral neuronal subtypes in zebrafish.…”