The Snail family of transcription factors has previously been implicated in the differentiation of epithelial cells into mesenchymal cells (epithelial-mesenchymal transitions) during embryonic development. Epithelial-mesenchymal transitions are also determinants of the progression of carcinomas, occurring concomitantly with the cellular acquisition of migratory properties following downregulation of expression of the adhesion protein E-cadherin. Here we show that mouse Snail is a strong repressor of transcription of the E-cadherin gene. Epithelial cells that ectopically express Snail adopt a fibroblastoid phenotype and acquire tumorigenic and invasive properties. Endogenous Snail protein is present in invasive mouse and human carcinoma cell lines and tumours in which E-cadherin expression has been lost. Therefore, the same molecules are used to trigger epithelial-mesenchymal transitions during embryonic development and in tumour progression. Snail may thus be considered as a marker for malignancy, opening up new avenues for the design of specific anti-invasive drugs.

Sensory circuits in the dorsal spinal cord integrate and transmit multiple cutaneous sensory modalities including the sense of light touch. Here we identify a population of excitatory interneurons (INs) in the dorsal horn that are important for transmitting innocuous light touch sensation. These neurons express the ROR alpha (RORα) nuclear orphan receptor and are selectively innervated by cutaneous low threshold mechanoreceptors (LTMs). Targeted removal of RORα INs in the dorsal spinal cord leads a marked reduction in behavioral responsiveness to light touch without affecting responses to noxious and itch stimuli. RORα IN-deficient mice also display a selective deficit in corrective foot movements. This phenotype, together with our demonstration that the RORα INs are innervated by corticospinal and vestibulospinal projection neurons, argues that the RORα INs direct corrective reflex movements by integrating touch information with descending motor commands from the cortex and cerebellum.

In the developing central nervous system, cellular diversity depends in part on organising signals that establish regionally restricted progenitor domains, each of which produces distinct types of differentiated neurons. However, the mechanisms of neuronal subtype specification within each progenitor domain remain poorly understood. The p2 progenitor domain in the ventral spinal cord gives rise to two interneuron (IN) subtypes, V2a and V2b, which integrate into local neuronal networks that control motor activity and locomotion. Foxn4, a forkhead transcription factor, is expressed in the common progenitors of V2a and V2b INs and is required directly for V2b but not for V2a development. We show here in experiments conducted using mouse and chick that Foxn4 induces expression of delta-like 4 (Dll4) and Mash1 (Ascl1). Dll4 then signals through Notch1 to subdivide the p2 progenitor pool. Foxn4, Mash1 and activated Notch1 trigger the genetic cascade leading to V2b INs, whereas the complementary set of progenitors, without active Notch1, generates V2a INs. Thus, Foxn4 plays a dual role in V2 IN development: (1) by initiating Notch-Delta signalling, it introduces the asymmetry required for development of V2a and V2b INs from their common progenitors; (2) it simultaneously activates the V2b genetic programme.

Animals depend on sensory feedback from mechanosensory afferents for the dynamic control of movement. This sensory feedback needs to be selectively modulated in a task- and context-dependent manner. Here, we show that inhibitory interneurons (INs) expressing the RORβ orphan nuclear receptor gate sensory feedback to the spinal motor system during walking and are required for the production of a fluid locomotor rhythm. Genetic manipulations that abrogate inhibitory RORβ IN function result in an ataxic gait characterized by exaggerated flexion movements and marked alterations to the step cycle. Inactivation of RORβ in inhibitory neurons leads to reduced presynaptic inhibition and changes to sensory-evoked reflexes, arguing that the RORβ inhibitory INs function to suppress the sensory transmission pathways that activate flexor motor reflexes and interfere with the ongoing locomotor program. VIDEO ABSTRACT.

Interneurons in the dorsal spinal cord process and relay innocuous and nociceptive somatosensory information from cutaneous receptors that sense touch, temperature and pain. These neurons display a well-defined organization with respect to their afferent innervation. Nociceptive afferents innervate lamina I and II, while cutaneous mechanosensory afferents primarily innervate sensory interneurons that are located in lamina III–IV. In this study, we outline a combinatorial transcription factor code that defines nine different inhibitory and excitatory interneuron populations in laminae III–IV of the postnatal cord. This transcription factor code reveals a high degree of molecular diversity in the neurons that make up laminae III–IV, and it lays the foundation for systematically analyzing and manipulating these different neuronal populations to assess their function. In addition, we find that many of the transcription factors that are expressed in the dorsal spinal cord at early postnatal times continue to be expressed in the adult, raising questions about their function in mature neurons and opening the door to their genetic manipulation in adult animals.

The neural crest constitutes a complex population of cells that originates at the edges of the neural plate of vertebrate embryos and gives rise to a high diversity of tissues and cell types. Molecular markers are very useful to identify cell populations, and in the case of the neural crest at early stages, many of them have been described. Here, we show a series of chicken embryos double labeled for several of the most commonly used crest markers that evidence the existence of different subpopulations. Slug is a very good marker for premigratory and early migratory cranial neural crest, RhoB labels delaminating cells and the very early migratory population, and the HNK-1 epitope is acquired in the migratory crest cells at a distance from the neural tube, with a significant proportion of the Slug-expressing migratory cells negative for HNK-1. The existence of these crest subpopulations should be considered when analyzing both wild-type embryos and the phenotype of experimentally manipulated chick embryos. Developmental Dynamics 229:136 -139, 2004.

The Snail gene family of transcription factors plays crucial roles in different morphogenetic processes during the development of vertebrate and invertebrate embryos. In previous studies of function interference for one of the family members, Slug, we showed its involvement and neural crest formation in the chick embryo. Now we have carried out a series of gain-of-function experiments in which we show that Slug overexpression in the neural tube of the chick embryo induces an increase in neural crest production. The analysis of electroporated embryos shows that Slug can induce the expression of rhoB and an increase in the number of HNK-1-positive migratory cells, indicating that it lies upstream of them in the genetic cascade of neural crest development. The increase in neural crest production after Slug overexpression was confined to the cranial region, indicating that the mechanisms of crest induction somehow differ between head and trunk. The expression of the two vertebrate family members, Slug and Snail, is peculiar with respect to the neural crest. Slug is not expressed in the premigratory crest in the mouse, whereas it is expressed in this cell population in the chick and the opposite is true for Snail(Sefton, M., Sánchez, S. and Nieto M. A. (1998) Development125, 3111-3121). This raises the question of whether they can be functionally equivalent. To test this hypothesis both intra- and interspecies, we have performed a series of ectopic expression experiments by electroporating chick and mouse Snail in the chick embryo hindbrain. We observe that both genes elicit the same responses in the neural tube. Our results indicate that they can be functionally equivalent, although the embryos show a higher response to the endogenous gene, chick Slug.