Biology subjects

Sagerstrom, C.

Publications and source records attributed to Sagerstrom, C..

3 recordsLinked to original sources

bioRxiv2026

Autonomous Dampening of Wnt Signaling Selects Zebrafish Spinal Cord Progenitors for an Oligodendrocyte Fate

Nervous system development relies on coordinated formation of neurons and glia from neural progenitor cells (NPCs). During spinal cord development, NPCs in the pMN domain of the ventral spinal cord produce motor neurons followed by oligodendrocyte precursor cells (OPCs), a subset of which differentiate as oligodendrocytes, the myelinating cell of the vertebrate central nervous system. Whereas prior research has outlined an extensive gene regulatory network driving oligodendrocyte lineage cell differentiation, less is known about the mechanisms that specify NPCs for oligodendrocyte fate. To elucidate these mechanisms, our lab recently generated a single-cell RNA sequencing and single-cell ATAC sequencing multi-omics dataset from the zebrafish spinal cord. The dataset identified a molecularly distinct subset of NPCs that appear fated to the oligodendrocyte lineage, which we refer to as pre-OPCs. Our data revealed that pre-OPCs are enriched for RNAs encoding factors that antagonize Wnt signaling, such as barhl2 and cachd1. The chromatin regions associated with these genes are highly accessible in pre-OPCs, suggesting that their expression is developmentally regulated. Using confocal light microscopy to visualize expression of a Wnt-responsive transgenic reporter, we found that Wnt signaling is downregulated in the spinal cord immediately prior to OPC specification. To explore how modulation of Wnt signaling influences OPC specification, we pharmacologically inhibited or activated Wnt signaling immediately prior to OPC specification. These experiments revealed that embryos treated with a Wnt inhibitor produced excess OPCs whereas those treated with a Wnt agonist had a deficit of OPCs. Additionally, CRISPR/Cas9 targeted mutations of barhl2 and cachd1 impaired OPC production. Finally, we identified wnt4b as a ventral source of Wnt and determined that loss of wnt4b enhances OPC specification. Together, our studies reveal pre-OPC modulation of ventral Wnt signaling as a mechanism of OPC specification in the spinal cord.

developmental biology↗

bioRxiv2025

Gsx2 Regulates Oligodendrocyte Precursor Formation in the Zebrafish Spinal Cord

Nervous system development relies on sequential and coordinated formation of diverse neurons and glia from neural progenitor cells (NPCs). In the spinal cord, NPCs of the pMN domain produce neurons early in development followed by oligodendrocyte precursor cells (OPCs), which subsequently differentiate as oligodendrocytes (OLs), the myelinating glia of the central nervous system, later in development. The mechanisms that specify neural progenitor cells to the OL lineage are not yet well understood. Using zebrafish as an experimental model system, we generated single-cell RNA sequencing and single-nuclei ATAC sequencing data that identified a subpopulation of NPCs, called pre-OPCs, that appeared fated to produce OPCs. pre-OPCs uniquely express several genes that encode transcription factors specific to the OL lineage, including Gsx2, which regulates OPC formation in the mouse forebrain. To investigate Gsx2 function in zebrafish OPC specification, we used CRISPR/Cas9 genome editing to create gsx2 loss-of-function alleles. gsx2 homozygous mutant embryos initiated OPC formation prematurely and produced excess OPCs without altering OL differentiation. Using our single-nuclei multi-omics dataset, we predicted a gene regulatory network centered around gsx2 and identified genes that might be transcriptionally regulated by Gsx2. Taken together, our studies suggest that Gsx2 expression in pre-OPCs contributes to the timing of OPC specification.

developmental biology↗

bioRxiv2019

HOX paralogs selectively convert binding of ubiquitous transcription factors into tissue-specific patterns of enhancer activation

Gene expression programs determine cell fate in embryonic development and their dysregulation results in disease. Transcription factors (TFs) control gene expression by binding to enhancers, but how TFs select and activate their target enhancers is still unclear. HOX TFs share conserved homeodomains with highly similar sequence recognition properties, yet they impart the identity of different animal body parts. To understand how HOX TFs control their specific transcriptional programs in vivo, we compared HOXA2 and HOXA3 binding profiles in the mouse embryo. HOXA2 and HOXA3 directly cooperate with TALE TFs and selectively target different subsets of a broad TALE chromatin platform. Binding of HOX and tissue-specific TFs convert low affinity TALE binding into high confidence, tissue-specific binding events, which bear the mark of active enhancers. We propose that HOX paralogs, alone and in combination with tissue-specific TFs, generate tissue-specific transcriptional outputs by modulating the activity of TALE TFs at selected enhancers.

developmental biology↗