A zinc finger protein that regulates oligodendrocyte specification, migration, and myelination in zebrafish

Abstract

Precise control of oligodendrocyte migration and development is crucial for myelination of axons in the central nervous system (CNS), but important questions remain unanswered about the mechanisms controlling these processes. In a zebrafish screen for myelination mutants, we identified a mutation in zinc finger protein 16-like (znf16l). znf16l mutant larvae have reduced myelin basic protein (mbp) expression and reduced CNS myelin. Marker, time-lapse and ultrastructural studies indicated that oligodendrocyte specification, migration and myelination are disrupted in znf16l mutants. Transgenic studies indicated that znf16l acts autonomously in oligodendrocytes. Expression of Zfp488 from mouse rescued mbp expression in znf16l mutants, indicating that these homologs have overlapping functions. Our results defined the function of a new zinc finger protein with specific function in oligodendrocyte specification, migration and myelination in the developing CNS.

High-throughput behavioral assay to investigate seizure sensitivity in zebrafish implicatesZFHX3in epilepsy

“…Since zfhx3 is a transcription factor, its transcript is unlikely to be observed in the axons of neurons, raising the possibility that zfhx3 is expressed in oligodendrocytes precursor cells (OPCs) which show overlapping expression domains (Brosamle & Halpern, 2002; Preston & Macklin, 2015; Schebesta & Serluca, 2009; Sidik & Talbot, 2015). Once OPCs reach their target axons they may differentiate immediately or wait until much later stages to differentiate into mature oligodendrocytes (highly specialized glial cells) which help stabilize axon tracts and increase conduction speed by wrapping the tracts in myelin sheaths (Brosamle & Halpern, 2002; Preston & Macklin, 2015; Sidik & Talbot, 2015; Young et al, 2013). While by 2 dpf, genetic markers for mature oligodendrocytes can be detected in the hindbrain and nascent myelin can be detected by 3–4 dpf in larval zebrafish (Brosamle & Halpern, 2002; Preston & Macklin, 2015; Sidik & Talbot, 2015), expression of zfhx3 is decreased in regions that have likely undergone oligodendrocyte maturation.…”

“…Once OPCs reach their target axons they may differentiate immediately or wait until much later stages to differentiate into mature oligodendrocytes (highly specialized glial cells) which help stabilize axon tracts and increase conduction speed by wrapping the tracts in myelin sheaths (Brosamle & Halpern, 2002; Preston & Macklin, 2015; Sidik & Talbot, 2015; Young et al, 2013). While by 2 dpf, genetic markers for mature oligodendrocytes can be detected in the hindbrain and nascent myelin can be detected by 3–4 dpf in larval zebrafish (Brosamle & Halpern, 2002; Preston & Macklin, 2015; Sidik & Talbot, 2015), expression of zfhx3 is decreased in regions that have likely undergone oligodendrocyte maturation. Therefore, Zfhx3 may play a role in OPC migration or differentiation.…”

Developmental regulation of zinc homeostasis in differentiating oligodendrocytes

“…There are numerous compartments that might be sequestering zinc and making it inaccessible to chromis-1. The nucleus contains many zinc-finger transcription factors important in myelination programs, such as Ying-Yang-1 (He et al, 2008), myelin transcription factor 1 (Myt1) (Nielsen et al, 2004;Besold and Michel, 2015), Zfp488 (Wang et al, 2006;Soundarapandian et al, 2011), Znf161 (Sidik and Talbot, 2015), Zfp24 (Elbaz et al, 2018), andZfp276 (Aberle et al, 2022). Nuclear zinc has also been implicated in control of epigenetic modifications (Krapivinsky et al, 2014) and these are well established to be important in controlling differentiation programs in OLs (Samudyata et al, 2020).…”

Transgenic fluorescent zebrafish lines that have revolutionized biomedical research

“…This line visualizes progenitor cells and radial glia (RG) of the pMN domain, motor neurons (MNs), oligodendrocyte lineage cells in the spinal cord at early developmental stages, and oligodendrocytes (OLs) in the adult stage [ 150 ]. It has been extensively used to study the developmental mechanisms of MNs and OLs from olig2 + progenitor cells [ 148 , 151 ], regeneration of MNs after injury [ 152 , 153 ] and the specification and differentiation of OLs [ 154 ]. In addition, this transgenic line has been exploited to mark cerebrospinal fluid contacting neurons in the spinal cord [ 155 ] and eurydendroid cells in the cerebellum [ 156 ].…”