GABAergic interneurons migrate long distances through stereotyped migration programs toward specific laminar positions. During their migration, GABAergic interneurons are morphologically alike but ...then differentiate into a rich array of interneuron subtypes critical for brain function. How interneuron subtypes acquire their final phenotypic traits remains largely unknown. Here, we show that cerebellar molecular layer GABAergic interneurons, derived from the same progenitor pool, use separate migration paths to reach their laminar position and differentiate into distinct basket cell (BC) and stellate cell (SC) GABAergic interneuron subtypes. Using two-photon live imaging, we find that SC final laminar position requires an extra step of tangential migration supported by a subpopulation of glutamatergic granule cells (GCs). Conditional depletion of GCs affects SC differentiation but does not affect BCs. Our results reveal how timely feedforward control of inhibitory interneuron migration path regulates their terminal differentiation and, thus, establishment of the local inhibitory circuit assembly.
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•Basket cells and stellate cells use stereotyped migration paths in cerebellum•Stellate cells migrate tangentially in the external granule cell layer•Immature granule cell neurites support stellate cell tangential migration•Genetic depletion of granule cells affects stellate cell differentiation
Cadilhac et al. report that molecular layer GABAergic progenitors use distinct migration paths to reach their laminar position in the cerebellum where they differentiate into basket cells (BCs) and stellate cells (SCs). SCs perform an additional tangential migration step along immature granule cell neurites whose genetic depletion mainly affects SC differentiation.
The developmental process and unique molecular identity between the many different types of dorsal root ganglion (DRG) sensory neurons generated during embryogenesis provide the cellular basis for ...the distinct perceptual modalities of somatosensation. The mechanisms leading to the generation of different types of nociceptive sensory neurons remain only partly understood. Here, we show that the transcription factor Cux2 is a novel marker of sensory neuron subpopulations of three main sublineages as defined by the expression of neurotrophic factor receptors TrkA, TrkB and TrkC. In particular, it is expressed in a subpopulation of early TrkA
+ neurons that arise during the early, Ngn1-independent initiated neurogenesis in the DRG. Postnatally, Cux2 marks a specific subtype of A-delta nociceptors as seen by expression of TrkA and NF200 but absence of TrpV1. Analysis of Cux2 mutant mice shows that Cux2 is not required for specification of Trk
+ neuronal subpopulations. However, Cux2 mutant mice are hypersensitive to mechanical, but not to heat or cold stimuli, consistent with a requirement in the process of specification of the mechanoreceptive neuron circuit. Hence, our results show that Cux2 is expressed and may participate in development of a specific subtype of myelinated TrkA
+ nociceptors.
► Cux2 is expressed in post-mitotic neurons in dorsal root ganglia. ► Cux2 is a novel marker of sensory neurons of the TrkA, TrkB and TrkC sublineages. ► Cux2 is expressed in a subpopulation of early TrkA
+ neurons. ► Postnatally, Cux2 marks a specific subtype of A-delta nociceptors. ► Cux2 mutant mice are hypersensitive to mechanical stimuli.
Touch sensation is mediated by specific subtypes of sensory neurons which develop in a hierarchical process from common early progenitor neurons, but the molecular mechanism that underlies ...diversification of touch‐sensitive mechanoreceptive neurons is not fully known. Here, we use genetically manipulated mice to examine whether the transcription factor short stature homeobox 2 (Shox2) participates in the acquisition of neuronal subtypes conveying touch sensation. We show that Shox2 encodes the development of category I low‐threshold mechanoreceptive neurons in glabrous skin, i.e. discriminative touch‐sensitive neurons which form innervations of epidermal Merkel cell and Meissner corpuscles. In contrast, other sensory fiber endings, including those innervating Pacinian corpuscles, are not dependent on Shox2. Shox2 is expressed in neurons of most or all classes of sensory neurons at early embryonic stages and is later confined to touch‐sensitive neurons expressing Ret and/or TrkB. Conditional deletion of Shox2 and analysis of Runx3−/−;Bax−/− mutant mice reveals that Runx3 is suppressing Shox2 while Shox2 is necessary for TrkB expression, and that these interactions are necessary for diversification of TrkB+ and TrkC+ mechanoreceptive neurons. In particular, development of TrkB+/Ret+ and TrkB+/Ret− touch‐sensitive neurons is critically dependent on Shox2. Consistently, Shox2 conditional mutant mice demonstrate a dramatic impairment of light touch responses. These results show that Shox2 is required for specification of a subclass of TrkB+ sensory neurons which convey the sensation of discriminative touch arising from stimuli of the skin.
Touch sensation is mediated by specific subtypes of sensory neurons which develop in a hierarchical process from common early progenitor neurons, but the molecular mechanism that underlies diversification of touch‐sensitive mechanoreceptive neurons is not fully known. Here, we use genetically manipulated mice to examine whether the transcription factor short stature homeobox 2 (Shox2) participates in the acquisition of neuronal subtypes conveying touch sensation.
The roof plate (RP) of the midbrain shows an unusual plasticity, as it is duplicated or interrupted by experimental manipulations involving the mid/hindbrain organizer or FGF8. In previous ...experiments, we have found that FGF8 induces a local patterning center, the isthmic node, that is essential for the local development of a RP. Here, we show that the plasticity of the midbrain RP derives from two apparently antagonistic influences of FGF8. On the one hand, FGF8 widens beyond the neural folds the competence of the neuroepithelium to develop a RP by inducing the expression of LMX1B and WNT1. Ectopic overexpression of these two factors is sufficient to induce widely the expression of markers of the mature RP in the midbrain. On the other hand, FGF8 exerts a major destabilizing influence on RP maturation by controlling signaling by members of the TGFbeta superfamily belonging to the BMP, GDF and activin subgroups. We show in particular that FGF8 tightly modulates follistatin expression, thus progressively restraining the inhibitory influence of activin B on RP differentiation. These regulations, together with FGF8 triggered apoptosis, allow the formation of a RP progress zone at some distance from the FGF8 source. Posterior elongation of the RP is permitted when the source of FGF8 withdraws. Growth of the posterior midbrain neuroepithelium and convergent extension movements induced by FGF8 both contribute to increase the distance between the source of FGF8 and the maturing RP. Normally, the antagonistic regulatory interactions spread smoothly across the midbrain. Plasticity of midbrain RP differentiation probably results from an experimentally induced imbalance between regulatory pathways.
The LIM domain is a cysteine-rich zinc-finger motif found in a large family of proteins. In LIM-homeodomain (LIM-hd) transcription factors and LIM-only (LMO) factors, the LIM domains are responsible ...for key interactions with co-activators, co-repressors, competitors, and other transcription factors, and are therefore of considerable importance for the regulation of associated transcriptional activity. In this review, the authors describe the progressive discoveries of NLI/Ldb/CLIM, LMO and RLIM, and discuss how the field was very recently updated by the finding that LIM-hd transcriptional activity is controlled by regulated degradation of cofactors and LIM-hd themselves.
Quel rôle jouèrent les Flamands dans la naissance de la « nation France » ? Que savait de Bouvines, Courtrai, Cassel ou Roosebeke, marqueurs mémoriels de cinq siècles d’histoire entre le comté de ...Flandre et le royaume de France, le clerc breton ou le noble provençal ? Que disait-on en Normandie ou en Auvergne, de la Flandre, des Flamands, de leur identité mais aussi de leur appartenance au royaume ? Les Français – ou tout au moins leurs élites – partageaient-ils avec le roi et avec ceux qui gravitaient à l’ombre de son pouvoir une perception commune de cette « question flamande » qui, des Carolingiens aux Valois, fut récurrente et souvent brûlante ? Le récit que l’on poursuit ici est moins celui des événements tels qu’ils se sont déroulés, que celui de la construction « imaginée » du passé qu’offrent les chroniques médiévales et, à leur suite à partir du xvie siècle, une grande variété de textes dont l’ambition fut de raconter à un public appelé peu à peu à former une nation une « histoire de France par la mémoire ».
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