Role of Robo1 receptor in semaphorin signalling system and cortical interneuron migration

En route to the cerebral cortex, interneurons encounter the developing striatum and avoid it. It has been shown that these cells express neuropilin (Nrp) as well as PlexinA receptors, which allow these cells to respond to Sema3A and Sema3F chemorepulsive cues expressed in the developing striatum and as consequence they migrate around it and into their proper tangential migratory paths. Robo proteins (receptors for the chemorepulsive family of ligands Slit) have also been observed in cortical interneurons, and they are thought to modulate the morphology of migrating interneurons as well as to play a role in their migration. In the present work, I found that Robo1, but not Robo2 or Slit1/Slit2, deficient (Robo1-/-) mice contain a significant number of cortical interneurons migrating aberrantly through their developing striatum. In vitro experiments showed that dissociated cells taken from the medial ganglionic eminence (MGE, major source of cortical interneurons) of Robo1-/- mice do not respond to either Sema3A or Sema3F induced chemorepulsion. Moreover, I observed significant down regulation of Nrp and PlexinA receptors, as well as reduced levels of Sema3F expression and of some intracellular effectors activated by Sema3A and Sema3F in Robo1-/- cortical interneurons. Using a cell line as an in vitro model, I confirmed that perturbation of Robo1 signalling results in loss of responsiveness to Sema3A and Sema3F, as well as down regulation of their receptors. Additionally, I found that Robo1 can bind directly to Nrp and PlexinA proteins. Taken together, the data presented here suggest a novel role for Robo1 receptor in controlling the expression of distinct components of the class 3 semaphorin signalling system and thus, the migration of cortical interneurons. They also suggest that the migration of cortical interneurons around the striatum might result from the collaborative effort of Robo1receptors and the class 3 semaphorin signalling system

CO(2) in the spotlight

Optogenetic techniques have revealed that retrotrapezoid neurons are essential for sensitivity to carbon dioxide

The dorsal spinal cord and hindbrain: from developmental mechanisms to functional circuits

Neurons of the dorsal hindbrain and spinal cord are central in receiving, processing and relaying sensory perception and participate in the coordination of sensory-motor output. Numerous cellular and molecular mechanisms that underlie neuronal development in both regions of the nervous system are shared. We discuss here the mechanisms that generate neuronal diversity in the dorsal spinal cord and hindbrain, and emphasize similarities in patterning and neuronal specification. Insight into the developmental mechanisms has provided tools that can help to assign functions to small subpopulations of neurons. Hence, novel information on how mechanosensory or pain sensation is encoded under normal and neuropathic conditions has already emerged. Such studies show that the complex neuronal circuits that control perception of somatosensory and viscerosensory stimuli are becoming amenable to investigations

Quantitative proteomics reveals dynamic interaction of c-Jun N-terminal kinase (JNK) with RNA transport granule proteins splicing factor proline- and glutamine-rich (Sfpq) and non-POU domain-containing octamer-binding protein (Nono) during neuronal differentiation

The c-Jun N-terminal kinase (JNK) is an important mediator of physiological and pathophysiological processes in the central nervous system. Importantly, JNK is not only involved in neuronal cell death but also plays a significant role in neuronal differentiation and regeneration. For example, nerve growth factor (NGF) induces JNK-dependent neuronal differentiation in several model systems. The mechanism how JNK mediates neuronal differentiation is not well understood. Here, we employ a proteomic strategy to better characterize the function of JNK during neuronal differentiation. We use SILAC-based quantitative proteomics to identify proteins that interact with JNK in PC12 cells in an NGF-dependent manner. Intriguingly, we find that JNK interacts with neuronal transport granule proteins such as Sfpq and Nono upon NGF treatment. We validate the specificity of these interactions by showing that they are disrupted by a specific peptide inhibitor that blocks the interaction of JNK with its substrates. Immunoprecipitation and western blotting experiments confirm the interaction of JNK1 with Sfpq/Nono and demonstrate that it is RNA dependent. Confocal microscopy and subcellular fractionation indicates that JNK1 associates with neuronal granule proteins in the cytosol of PC12 cells, primary cortical neurons and P19-neuronal cells. Finally, siRNA experiments confirm that Sfpq is necessary for neuronal outgrowth in PC12 cells and that it is most likely acting in the same pathway as JNK. In summary, our data indicate that the interaction of JNK1 with transport granule proteins in the cytosol of differentiating neurons plays an important role during neuronal development

Transcription factors regulating the specification of brainstem respiratory neurons

Breathing (or respiration) is an unconscious and complex motor behavior which neuronal drive emerges from the brainstem. In simplistic terms, respiratory motor activity comprises two phases, inspiration (uptake of oxygen, O(2)) and expiration (release of carbon dioxide, CO(2)). Breathing is not rigid, but instead highly adaptable to external and internal physiological demands of the organism. The neurons that generate, monitor, and adjust breathing patterns locate to two major brainstem structures, the pons and medulla oblongata. Extensive research over the last three decades has begun to identify the developmental origins of most brainstem neurons that control different aspects of breathing. This research has also elucidated the transcriptional control that secures the specification of brainstem respiratory neurons. In this review, we aim to summarize our current knowledge on the transcriptional regulation that operates during the specification of respiratory neurons, and we will highlight the cell lineages that contribute to the central respiratory circuit. Lastly, we will discuss on genetic disturbances altering transcription factor regulation and their impact in hypoventilation disorders in humans

Insm1 controls development of pituitary endocrine cells and requires a SNAG domain for function and for recruitment of histone-modifying factors

The Insm1 gene encodes a zinc finger factor expressed in many endocrine organs. We show here that Insm1 is required for differentiation of all endocrine cells in the pituitary. Thus, in Insm1 mutant mice, hormones characteristic of the different pituitary cell types (thyroid-stimulating hormone, follicle-stimulating hormone, melanocyte-stimulating hormone, adrenocorticotrope hormone, growth hormone and prolactin) are absent or produced at markedly reduced levels. This differentiation deficit is accompanied by upregulated expression of components of the Notch signaling pathway, and by prolonged expression of progenitor markers, such as Sox2. Furthermore, skeletal muscle-specific genes are ectopically expressed in endocrine cells, indicating that Insm1 participates in the repression of an inappropriate gene expression program. Because Insm1 is also essential for differentiation of endocrine cells in the pancreas, intestine and adrenal gland, it is emerging as a transcription factor that acts in a pan-endocrine manner. The Insm1 factor contains a SNAG domain at its N-terminus, and we show here that the SNAG domain recruits histone-modifying factors (Kdm1a, Hdac1/2 and Rcor1-3) and other proteins implicated in transcriptional regulation (Hmg20a/b and Gse1). Deletion of sequences encoding the SNAG domain in mice disrupted differentiation of pituitary endocrine cells, and resulted in an upregulated expression of components of the Notch signaling pathway and ectopic expression of skeletal muscle-specific genes. Our work demonstrates that Insm1 acts in the epigenetic and transcriptional network that controls differentiation of endocrine cells in the anterior pituitary gland, and that it requires the SNAG domain to exert this function in vivo