SUMMARY Itch is the least well understood of all the somatic senses, and the neural circuits that underlie this sensation are poorly defined. Here we show that the atonal-related transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord and appears to play a role in the formation and regulation of pruritic (itch) circuits. Mice lacking Bhlhb5 develop self-inflicted skin lesions and show significantly enhanced scratching responses to pruritic agents. Through genetic fate-mapping and conditional ablation we provide evidence that the pruritic phenotype in Bhlhb5 mutants may be due to selective loss of a subset of inhibitory interneurons in the dorsal horn. Our findings suggest that Bhlhb5 is required for the survival of a specific population of inhibitory interneurons that regulate pruritis and provide evidence that the loss of inhibitory synaptic input results in abnormal itch.

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.

Retinal bipolar (BP) cells mediate the earliest steps in image processing in the visual system, but the genetic pathways that regulate their development and function are incompletely known. We identified PRDI-BF1 and RIZ homology domain containing 8 (PRDM8) as a highly conserved transcription factor that is abundantly expressed in mouse retina. During development and in maturity, PRDM8 is expressed strongly in BP cells and a fraction of amacrine and ganglion cells. To determine whether Prdm8 is essential to BP cell development or physiology, we targeted the gene in mice. Prdm8 EGFP/EGFP mice showed nonprogressive b-wave deficits on electroretinograms, consistent with compromised BP cell function or circuitry resembling the incomplete form of human congenital stationary night blindness (CSNB). BP cell specification was normal in Prdm8 EGFP/EGFP retina as determined by VSX2 + cell numbers and retinal morphology at postnatal day 6. BP subtype differentiation was impaired, however, as indicated by absent or diminished expression of BP subtype-specific markers, including the putative PRDM8 regulatory target PKCα (Prkca) and its protein. By adulthood, rod bipolar (RB) and type 2 OFF-cone bipolar (CB) cells were nearly absent from Prdm8-null mice. Although no change was detected in total amacrine cell (AC) numbers, increased PRKCA + and cholinergic ACs and decreased GABAergic ACs were seen, suggesting an alteration in amacrine subtype identity. These findings establish that PRDM8 is required for RB and type 2 OFF-CB cell survival and amacrine subtype identity, and they present PRDM8 as a candidate gene for human CSNB.retina | bipolar cell | amacrine cell | genetics | development R etinal bipolar (BP) cells are the first interneurons in the mammalian visual signaling pathway, connecting photoreceptors (PRs) to ganglion cells and then, through the optic nerve, to the brain. In mouse retina, 13 BP subtypes are distinguished by their (i) predominant presynaptic (rod or cone) input, (ii) morphology (axon length and terminal field width), (iii) functional response to increased illumination (depolarizing or ON-BP cells and hyperpolarizing or OFF-BP cells), and (iv) molecular markers (1). Mouse retina has only one type of rod BP (RB) cell, primarily postsynaptic to rod PRs, which extends its axon to the innermost sublamina of the inner plexiform layer (IPL) and depolarizes in response to increments in illumination. The axons of cone BP (CB) cells ramify throughout the IPL, but those that terminate in the outer sublaminae are functionally OFF-CB cells that hyperpolarize to light increments, whereas those that terminate in the inner sublaminae are ON-CB cells (1). Moreover, ON-and OFF-BP cells make direct and indirect synaptic connections with corresponding ON-and OFF-retinal ganglion cells (RGCs) in the IPL. The ON and OFF properties of BP cells result from differences in glutamate receptor activity on BP cell dendrites (1). Hence, the early integration of visual signals in the mammalian retina is determined by the specific syn...

Src tyrosine kinase phosphorylates the general transcription factor protein TFII-I, which is deleted in the neurodevelopmental disorder Williams-Beuren syndrome (WBS). We identified phenotypes such as increased sociability, visuospatial deficits, craniofacial abnormalities, and hyperactivity that overlap with symptoms of WBS in a mouse with disruption of Src.