Sulfatase 2 promotes generation of a spinal cord astrocyte subtype that stands out through the expression of Olig2

Abstract

Generation of glial cell diversity in the developing spinal cord is known to depend on spatio‐temporal patterning programs. In particular, expression of the transcription factor Olig2 in neural progenitors of the pMN domain is recognized as critical to their fate choice decision to form oligodendrocyte precursor cells (OPCs) instead of astrocyte precursors (APs). However, generating some confusion, lineage‐tracing studies of Olig2 progenitors in the spinal cord provided evidence that these progenitors also generate some astrocytes. Here, we addressed the role of the heparan sulfate‐editing enzyme Sulf2 in the control of gliogenesis and found an unanticipated function for this enzyme. At initiation of gliogenesis in mouse, Sulf2 is expressed in ventral neural progenitors of the embryonic spinal cord, including in Olig2‐expressing cells of the pMN domain. We found that sulf2 deletion, while not affecting OPC production, impairs generation of a previously unknown Olig2‐expressing pMN‐derived cell subtype that, in contrast to OPCs, does not upregulate Sox10, PDGFRα or Olig1. Instead, these cells activate expression of AP identity genes, including aldh1L1 and fgfr3 and, of note, retain Olig2 expression as they populate the spinal parenchyma at embryonic stages but also as they differentiate into mature astrocytes at postnatal stages. Thus, our study, by revealing the existence of Olig2‐expressing APs that segregate early from pMN cells under the influence of Sulf2, supports the existence of a common source of APs and OPCs in the ventral spinal cord and highlights divergent regulatory mechanism for the development of pMN‐derived OPCs and APs.

Sulf2a controls Shh-dependent neural fate specification in the developing spinal cord

“…Comparison of Sulf1 and Sulf2 mouse knockout phenotypes led to the conclusion that the two enzymes act in a similar way at the level of Shh source cells to regulate Shh-dependent patterning at the time of OPC specification 11 . However, supporting the view that Sulf2 has a unique and additional function, conditional depletion of Sulf2 specifically in neural progenitors expressing Olig2 but not in Shh source cells is sufficient to impair gliogenesis in mouse 26 . Whether this function is linked to regulation of the Shh signal remains an open question.…”

Sulf2a controls Shh-dependent neural fate specification in the developing spinal cord

“…The first main finding of our work is that, in contrast to other vertebrates where the different Sulfs display overlapping expression domains in the developing spinal cord 10,11,24-26 , in zebrafish, a subset of spinal neural progenitors only expresses Sulf2a throughout neurogenesis and gliogenesis. Starting out from this observation, studying the role of Sulf2a in zebrafish represented a unique opportunity to investigate the still debated question of whether Sulf proteins fulfill redundant functions or contribute differentially to spinal cord development 9,11,24 . During the neurogenic phase, which takes place between 10 and 30 hpf in the ventral zebrafish spinal cord 28 , we showed that Sulf2a prevents excess production of V3 interneurons and fosters MN generation.…”

“…Comparison of Sulf1 and Sulf2 mouse knockout phenotypes led to the conclusion that the two enzymes act in a similar way at the level of Shh source cells to regulate Shh-dependent patterning at the time of OPC specification 11 . However, supporting the view that Sulf2 has a unique and additional function, conditional depletion of Sulf2 specifically in neural progenitors expressing Olig2 but not in Shh source cells is sufficient to impair gliogenesis in mouse 24 . Whether this function is linked to regulation of the Shh signal remains an open question.…”

“…However, whether Sulf1 and Sulf2 exert specific roles in the developing spinal cord remains to be addressed. In this tissue, in contrast to Sulf1 whose expression is restricted to medial and lateral floor plate cells, Sulf2 is expressed broadly in both floor plate cells and neural progenitors 7-11,24-26 . Comparison of Sulf1 and Sulf2 mouse knockout phenotypes led to the conclusion that the two enzymes act in a similar way at the level of Shh source cells to regulate Shh-dependent patterning at the time of OPC specification 11 .…”

Region-specific Distribution of Olig2-expressing Astrocytes in Adult Mouse Brain and Spinal Cord

“…Different subtypes of astrocytes may be dependent on the differential combination of SLIT1 and Reelin under the regulation of different transcription factors activated by SHH signaling [3]. Interestingly, in the mouse spinal cord, a subpopulation of Olig2 + astrocyte progenitor cells are reported to be produced in the same region where oligodendrocytes are generated [7,10], which might explain why we observed a large number of Olig2 + astrocytes in the adult spinal cord. Besides produced directly from the transformation of radial glia cells, astrocytes can also be produced from the proliferation of differentiated astrocytes [3,21,22].…”