, 2010). Together, these studies raise the possibility that Bhlhb4 and Bhlhb5 are involved

in late aspects of neuronal differentiation, such as neural circuit assembly, that may be essential for neuronal survival. However, why certain neurons die in the absence of these transcriptional click here repressors is unknown, and this gap in knowledge stems in part from a lack of mechanistic understanding of how these transcription factors function in function in neural circuit formation. A possible clue to this puzzle comes from studies of Bhlhb5 in the dorsal telencephalon. In mice lacking Bhlhb5, neurons of the dorsal telencephalon survive and send out axons, but these projections fail to reach their targets. For instance, corticospinal motor neurons terminate prematurely along the pyramidal tract in the ventral hindbrain and none extend into the spinal cord ( Joshi et al., 2008).

Moreover, as we report here, Bhlhb5 mutants also show a complete absence of the three fiber tracts that connect the cerebral hemispheres, suggesting that axonal mistargeting in the absence of Bhlhb5 is a widespread phenomenon. Since mice lacking Bhlhb5 show axon targeting defects, we reasoned that one of the roles of Bhlhb5 in the dorsal telencephalon may be to regulate neuronal connectivity, Adriamycin ic50 perhaps by repressing specific genes until they are needed, thereby ensuring that genes are expressed at the right time and place for correct neural circuit assembly. To investigate this possibility, we identified the targets of the Bhlhb5 transcriptional repressor, hoping to elucidate how this transcription factor functions at a mechanistic level. Here, we show that Bhlhb5 functions by binding to specific DNA sequence elements and then recruiting the PR/SET domain-containing protein, Pr-domain 8 (Prdm8) to mediate the repression of target genes that must be repressed for neural circuits to form Protein kinase N1 correctly. Our observations suggest that Bhlhb5 and Prdm8 are obligate partners for key aspects of neuronal development and, consistent with this idea, we find that mice lacking either Bhlhb5 or Prdm8 have strikingly similar cellular

and behavioral abnormalities. We use genetic rescue experiments to demonstrate that one important target of the Prdm8/Bhlhb5 repressor complex is Cadherin-11 (Cdh11), a cell-cell adhesion molecule involved in neural circuit assembly. Taken together these experiments have revealed how a bHLH transcription factor associates with a PR/SET-domain repressor protein to regulate genes involved in the proper formation of neural circuits. To gain insight into how Bhlhb5 functions to regulate axon targeting, we sought to determine possible Bhlhb5 target genes by identifying genes that are misexpressed in Bhlhb5 mutant mice during the early development of the dorsal telencephalon (E13.5, E15.5, and E17.5). By expression profiling, we found a total of eight transcripts that were significantly misregulated (FDR < 0.05) when Bhlhb5 is disrupted.