Identification of Multiple Subsets of Ventral Interneurons and Differential Distribution along the Rostrocaudal Axis of the Developing Spinal Cord

The spinal cord contains neuronal circuits termed Central Pattern Generators (CPGs) that coordinate rhythmic motor activities. CPG circuits consist of motor neurons and multiple interneuron cell types, many of which are derived from four distinct cardinal classes of ventral interneurons, called V0, V1, V2 and V3. While significant progress has been made on elucidating the molecular and genetic mechanisms that control ventral interneuron differentiation, little is known about their distribution along the antero-posterior axis of the spinal cord and their diversification. Here, we report that V0, V1 and V2 interneurons exhibit distinct organizational patterns at brachial, thoracic and lumbar levels of the developing spinal cord. In addition, we demonstrate that each cardinal class of ventral interneurons can be subdivided into several subsets according to the combinatorial expression of different sets of transcription factors, and that these subsets are differentially distributed along the rostrocaudal axis of the spinal cord. This comprehensive molecular profiling of ventral interneurons provides an important resource for investigating neuronal diversification in the developing spinal cord and for understanding the contribution of specific interneuron subsets on CPG circuits and motor control

Cent scientifiques répliquent à SEA (Suppression des Expériences sur l’Animal vivant) et dénoncent sa désinformation

La lutte contre la maltraitance animale est sans conteste une cause moralement juste. Mais elle ne justifie en rien la désinformation à laquelle certaines associations qui s’en réclament ont recours pour remettre en question l’usage de l’expérimentation animale en recherche

Modifications des domaines d'expression de gènes du développement induites par l'acide rétinoïque sous la forme all-trans chez des embryons de souris cultivés in vitro

Doctorat en sciences biologiques -- UCL, 199

Control of hepatic differentiation by activin/TGFbeta signaling

During liver development, liver progenitors called hepatoblasts differentiate into hepatocytes or biliary cells. Recently, we showed that the segregation between hepatocytes and biliary cells is dependent on a gradient of Activin/TGFbeta signaling, and that Activin/TGFbeta signaling is controlled in fetal liver by transcription factors of the Onecut family. Here, we discuss candidate factors possibly involved in the formation of the Activin/TGFbeta signaling gradient, how this gradient could integrate into a network of signaling pathways modulating hepatoblast differentiation, and the implications for human liver disease and therapy

Generating spinal motor neuron diversity: a long quest for neuronal identity

Understanding how thousands of different neuronal types are generated in the CNS constitutes a major challenge for developmental neurobiologists and is a prerequisite before considering cell or gene therapies of nervous lesions or pathologies. During embryonic development, spinal motor neurons (MNs) segregate into distinct subpopulations that display specific characteristics and properties including molecular identity, migration pattern, allocation to specific motor columns, and innervation of defined target. Because of the facility to correlate these different characteristics, the diversification of spinal MNs has become the model of choice for studying the molecular and cellular mechanisms underlying the generation of multiple neuronal populations in the developing CNS. Therefore, how spinal motor neuron subpopulations are produced during development has been extensively studied during the last two decades. In this review article, we will provide a comprehensive overview of the genetic and molecular mechanisms that contribute to the diversification of spinal MNs

Guidance of motor axons: where do we stand?

Motor neurons are among the longest projection neurons and their axons extend into the periphery following highly stereotypical pathways. Motor neurons share similar guidance molecules with other projection neurons. Hence, one challenge in the field has been to understand how the vast complexity of connections can be regulated by a relatively small number of factors. In this review, we describe the transcriptional programs and signaling pathways that guide motor axons as they navigate toward their muscle targets. In particular, we underscore how signals triggered by these pathways are integrated in time and space to increase the diversity of the steering mechanisms and improve the accuracy of axon path finding

Dynamic expression of the Onecut transcription factors HNF-6, OC-2 and OC-3 during spinal motor neuron development.

The Onecut transcription factors, namely HNF-6, OC-2 and OC-3, are transcriptional activators expressed in liver, pancreas and nervous system during development. Although their expression and roles in endoderm-derived tissues and in the trigeminal ganglia have been investigated, their expression in the CNS has not been described yet. In this study, we report a qualitative and quantitative expression profile of the Onecut factors in the developing spinal motor neurons. We provide evidence that Onecut expression is initiated in newly-born motor neurons. At later stages, they are differentially and dynamically expressed in subsets of differentiating motor neuron within the four motor columns. We also show that the expression profile of HNF-6 in spinal motor neurons is conserved in chick embryos. Together, our data unveil a complex and dynamic expression profile of the Onecut proteins in spinal motor neurons, which suggests that these factors may participate in regulatory networks that control different steps of motor neuron development

CBP and p300 coactivators contribute to the maintenance of Isl1 expression by the Onecut transcription factors in embryonic spinal motor neurons.

Onecut transcription factors are required to maintain Islet1 (Isl1) expression in developing spinal motor neurons (MNs), and this process is critical for proper MN differentiation. However, the mechanisms whereby OC stimulate Isl1 expression remain unknown. CREB-binding protein (CBP) and p300 paralogs are transcriptional coactivators that interact with OC proteins in hepatic cells. In the embryonic spinal cord, CBP and p300 play key roles in neurogenesis and MN differentiation. Here, using chromatin immunoprecipitation and in ovo electroporation in chicken spinal cord, we provide evidence that CBP and p300 contribute to the regulation of Isl1 expression by the OC factors in embryonic spinal MNs. CBP and p300 are detected on the CREST2 enhancer of Isl1 where OC factors are also bound. Inhibition of CBP and p300 activity inhibits activation of the CREST2 enhancer and prevents the stimulation of Isl1 expression by the OC factors. These observations suggest that CBP and p300 coactivators cooperate with OC factors to maintain Isl1 expression in postmitotic MNs

Onecut factors control development of the Locus Coeruleus and of the mesencephalic trigeminal nucleus.

The Locus Coeruleus (LC), the main noradrenergic nucleus in the vertebrate CNS, contributes to the regulation of several processes including arousal, sleep, adaptative behaviors and stress. Regulators controlling the formation of the LC have been identified but factors involved in its maintenance remain unknown. Here, we show that members of the Onecut (OC) family of transcription factors, namely HNF-6, OC-2 and OC-3, are required for maintenance of the LC phenotype. Indeed, in embryos lacking any OC proteins, LC neurons properly differentiate but abnormally migrate and eventually lose their noradrenergic characteristics. Surprisingly, the expression of Oc genes in these neurons is restricted to the earliest differentiation stages, suggesting that OC factors may regulate maintenance of the LC in a non cell-autonomous manner. Accordingly, the OC factors are present throughout development in a population directly adjacent to the LC, the rhombencephalic portion of the mesencephalic trigeminal nucleus (MTN). In the absence of OC factors, rhombencephalic MTN neurons fail to be generated, suggesting that OC proteins cell-autonomously control their production. Hence, we propose that OC factors are required at early developmental stages for differentiation of the MTN neurons that are in turn necessary for maintenance of the LC