Voltage-gated ion channels have to be at the right place in the right number to endow individual neurons with their specific character. Their biophysical properties together with their spatial distribution define the signalling characteristics of a neuron. Improper channel localization could cause communication defects in a neuronal network. This review covers recent studies of mechanisms for targeting voltage-gated ion channels to axons and dendrites, including trafficking, retention and endocytosis pathways for the preferential localization of particular ion channels. We also discuss how the spatial localization of these channels might contribute to the electrical excitability of neurons, and consider the need for future work in this emerging field.

The spinal cord integrates and relays somatosensory input, leading to complex motor responses. Research over the past couple of decades has identified transcription factor networks that function during development to define and instruct the generation of diverse neuronal populations within the spinal cord. A number of studies have now started to connect these developmentally defined populations with their roles in somatosensory circuits. Here, we review our current understanding of how neuronal diversity in the dorsal spinal cord is generated and we discuss the logic underlying how these neurons form the basis of somatosensory circuits.

The human genome is far smaller than originally estimated, and one explanation is that alternative splicing creates greater proteomic complexity than a simple count of open reading frames would suggest. The p53 homologue p63, for example, is a tetrameric transcription factor implicated in epithelial development and expressed as at least six isoforms with widely differing transactivation potential. In particular, p63␣ isoforms contain a 27-kDa C-terminal region that drastically reduces their activity and is of clear biological importance, since patients with deletions in this C terminus have phenotypes very similar to patients with mutations in the DNA-binding domain. We have identified a novel domain within this C terminus that is necessary and sufficient for transcriptional inhibition and which acts by binding to a region in the N-terminal transactivation domain of p63 homologous to the MDM2 binding site in p53. Based on this mechanism, we provide a model that explains the transactivation potential of homo-and heterotetramers composed of different p63 isoforms and their effect on p53.

SUMMARY Generating a balanced network of inhibitory and excitatory neurons during development requires precise transcriptional control. In the dorsal spinal cord, Ptf1a, a basic helix-loop-helix (bHLH) transcription activator, maintains this delicate balance by inducing homeodomain (HD) transcription factors such as Pax2 to specify the inhibitory lineage, while suppressing HD factors such as Tlx1/3 that specify the excitatory lineage. We uncover the mechanism by which Ptf1a represses excitatory cell fate in the inhibitory lineage. We identify Prdm13 as a direct target of Ptf1a and reveal that Prdm13 actively represses excitatory cell fate by binding to regulatory sequences near the Tlx1 and Tlx3 genes to silence their expression. Prdm13 acts through multiple mechanisms including interactions with the bHLH factor Ascl1 to repress Ascl1 activation of Tlx3. Thus, Prdm13 is a key component of a highly coordinated transcriptional network that determines the balance of inhibitory versus excitatory neurons in the dorsal spinal cord.

Summary Proprioception, the sense of limb and body position, is essential for generating proper movement. Unconscious proprioceptive information travels through cerebellar-projecting neurons in the spinal cord and medulla. The progenitor domain defined by the basic helix-loop-helix (bHLH) transcription factor, ATOH1, has been implicated in forming these cerebellar-projecting neurons; however, their precise contribution to proprioceptive tracts and motor behavior is unknown. Significantly, we demonstrate that Atoh1-lineage neurons in the spinal cord reside outside Clarke’s column (CC), a main contributor of neurons relaying hindlimb proprioception, despite giving rise to the anatomical and functional correlate of CC in the medulla, the external cuneate nucleus (ECu), which mediates forelimb proprioception. Elimination of caudal Atoh1-lineages results in mice with relatively normal locomotion, but unable to perform coordinated motor tasks. Altogether, we reveal that proprioceptive nuclei in the spinal cord and medulla develop from more than one progenitor source suggesting an avenue to uncover distinct proprioceptive functions.

Voltage-gated potassium (Kv) channels, essential for regulating potassium uptake and cell volume in plants and electrical excitability in animals, switch between conducting and non-conducting states as a result of conformational changes in the four voltage-sensing domains (VSDs) that surround the channel pore. This process, known as gating, is initiated by a cluster of positively charged residues on the fourth transmembrane segment (S4) of each VSD, which drives the VSD into a 'down state' at negative voltages and an 'up state' at more positive voltages. The crystal structure of Kv1.2 probably corresponds to the up state, but the local environment of S4 in the down state and its motion in voltage gating remains unresolved. Here we employed several conditional lethal/second-site suppressor yeast screens to determine the transmembrane packing of the VSD in the down state. This screen relies on the ability of KAT1, a eukaryotic Kv channel, to conduct potassium when its VSDs are in the down state, thereby rescuing potassium-transport-deficient yeast. Starting with KAT1 channels bearing conditional lethal mutations, we identified second-site suppressor mutations throughout the VSD that recover yeast growth. We then constructed a down state model of the channel using six pairs of interacting residues as structural constraints and verified this model by engineering suppressor mutations on the basis of spatial considerations. A comparison of this down state model with the up state Kv1.2 structure suggests that the VSDs undergo large rearrangements during gating, whereas the S4 segment remains positioned between the central pore and the remainder of the VSD in both states.

Background: Neurogenesis requires neural progenitor cell (NPC) proliferation, neuronal migration, and differentiation. During embryonic development, neurons are generated in specific areas of the developing neuroepithelium and migrate to their appropriate positions. In the adult brain, neurogenesis continues in the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricle. Although neurogenesis is fundamental to brain development and function, our understanding of the molecular mechanisms that regulate neurogenesis is still limited. Results: In this study, we generated a Sox11 floxed allele and a Sox11 null allele in mice using the Cre-loxP technology. We first analyzed the role of the transcription factor Sox11 in embryonic neurogenesis using Sox11 null embryos. We also examined the role of Sox11 in adult hippocampal neurogenesis using Sox11 conditional knockout mice in which Sox11 is specifically deleted in adult NPCs. Sox11 null embryos developed small and disorganized brains, accompanied by transient proliferation deficits in NPCs. Deletion of Sox11 in adult NPCs blunted proliferation in the SGZ. Using functional genomics, we identified potential downstream target genes of Sox11. Conclusions: Taken together, our work provides evidence that Sox11 is required for both embryonic and adult neurogenesis, and identifies potential downstream target genes. Developmental Dynamics 242:638-653,

Highlights d PRDM12 is expressed in neural crest cells (NCCs) and all nociceptive lineage neurons d Inactivation of PRDM12 results in the absence of the entire nociceptive lineage d Forced expression of PRDM12 in NCCs represses nonnociceptor fates d PRDM12 regulates progenitor proliferation and the sensory neurogenesis program