Bhlhb5 and Prdm8 Form a Repressor Complex Involved in Neuronal Circuit Assembly

Abstract

SUMMARY Although transcription factors that repress gene expression play critical roles in nervous system development, their mechanism of action remains to be understood. Here we report that the Olig-related transcription factor Bhlhb5 (also known as Bhlhe22) forms a repressor complex with the PR/SET domain protein, Prdm8. We find that Bhlhb5 binds to sequence-specific DNA elements and then recruits Prdm8, which mediates the repression of target genes. This interaction is critical for repressor function since mice lacking either Bhlhb5 or Prdm8 have strikingly similar cellular and behavioral phenotypes, including axonal mistargeting by neurons of the dorsal telencephalon and abnormal itch-like behavior. We provide evidence that Cadherin-11 functions as a target of the Prdm8/Bhlhb5 repressor complex that must be repressed for proper neuronal development to occur. These findings suggest that Prdm8 is an obligate partner of Bhlhb5, forming a repressor complex that directs neural development in part through the precise regulation of Cadherin-11.

Human cerebral organoids recapitulate gene expression programs of fetal neocortex development

“…TUBB (tubulin, beta class I), a structural component of microtubules, was the most differentially expressed gene with higher expression in both progenitors and neurons in organoids. Other potentially relevant differences include PRDM8, which has a role in assembling neuronal circuits in upper layer cortical neurons (25), and NFIX, which is involved in progenitor cell differentiation (26), both of which have higher expression in fetal neuronal cells than in organoid cells. Most of these genes differed in both ESC-and iPSC-derived organoids relative to the fetal tissue.…”

The Prdm family: expanding roles in stem cells and development

“…Prdm3 may have a similar mode of action at the Pbx1 (pre-B-cell leukaemia homeobox 1) locus (Shimabe et al, 2009), and Prdm8 at the Cdh11 (cadherin 11) locus (Ross et al, 2012). Prdm8 is expressed in several regions of the developing nervous system (Table 2) (Kinameri et al, 2008;Komai et al, 2009) and is coexpressed in several places with the DNA sequence-specific bHLH (basic helix-loop-helix) transcription factor Bhlhb5 (Bhlhe22 -Mouse Genome Informatics) (Ross et al, 2012).…”

“…Mice lacking Prdm8 or Bhlhb5 have very similar behavioural phenotypes and defects in axon outgrowth. Bhlhb5 targets several loci involved in neuronal development, including Cdh11, where it recruits Prdm8 that in turn represses transcription (Ross et al, 2012); whether this is through the intrinsic H3K9 methyltransferase activity of Prdm8 is unclear (Eom et al, 2009).…”

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

“…Although we have not detected an ortholog of Zfp488 in the zebrafish genome, its characteristic structure of two zinc finger motifs flanking a nuclear localization signal is shared with another protein, PR domain containing 8 (Prdm8), that is conserved among zebrafish, mice and humans (Wang et al, 2006;Ross et al, 2012). Prdm8 has been shown to interact with Bhlhb5, a basic helix-loophelix protein related to Olig2, to form a repressor complex in the context of neurogenesis (Ross et al, 2012). It will be of interest to examine the role of prdm8 and the possibility that Prdm8 and Znf16l have overlapping functions in the control of oligodendrocyte specification, migration and myelination.…”

“…Likewise, our in vivo rescue experiments indicate that a mammalian homolog of znf16l, Zfp488, can substitute for znf16l despite their sequence divergence. Although we have not detected an ortholog of Zfp488 in the zebrafish genome, its characteristic structure of two zinc finger motifs flanking a nuclear localization signal is shared with another protein, PR domain containing 8 (Prdm8), that is conserved among zebrafish, mice and humans (Wang et al, 2006;Ross et al, 2012). Prdm8 has been shown to interact with Bhlhb5, a basic helix-loophelix protein related to Olig2, to form a repressor complex in the context of neurogenesis (Ross et al, 2012).…”