Morphogens act in developing tissues to control the spatial arrangement of cellular differentiation. The activity of a morphogen has generally been viewed as a concentration-dependent response to a diffusible signal, but the duration of morphogen signalling can also affect cellular responses. One such example is the morphogen sonic hedgehog (SHH). In the vertebrate central nervous system and limbs, the pattern of cellular differentiation is controlled by both the amount and the time of SHH exposure. How these two parameters are interpreted at a cellular level has been unclear. Here we provide evidence that changing the concentration or duration of SHH has an equivalent effect on intracellular signalling. Chick neural cells convert different concentrations of SHH into time-limited periods of signal transduction, such that signal duration is proportional to SHH concentration. This depends on the gradual desensitization of cells to ongoing SHH exposure, mediated by the SHH-dependent upregulation of patched 1 (PTC1), a ligand-binding inhibitor of SHH signalling. Thus, in addition to its role in shaping the SHH gradient, PTC1 participates cell autonomously in gradient sensing. Together, the data reveal a novel strategy for morphogen interpretation, in which the temporal adaptation of cells to a morphogen integrates the concentration and duration of a signal to control differential gene expression.

No abstract

During CNS development, the proliferation of progenitors must be coordinated with the pattern of neuronal subtype generation. In the ventral neural tube, Sonic hedgehog acts as a long range morphogen to organise the pattern of cell differentiation by controlling the activity of Gli transcription factors. Here, we provide evidence that the same pathway also acts directly at long range to promote the proliferation and survival of progenitor cells. Blockade of Shh signaling or inhibition of Gli activity results in cell autonomous decreases in progenitor proliferation and survival. Conversely, positive Gli activity promotes proliferation and rescues the effects of inhibiting Shh signaling. Analysis of neural cells indicates that Shh/Gli signaling regulates the G1 phase of cell cycle and the expression of the anti-apoptotic factor Bcl2. Furthermore, Shh signaling independently regulates patterning, proliferation and survival of neural cells, thus Shh/Gli activity couples these separate cellular responses of progenitors to coordinate neural development.

Adult hippocampal neurogenesis (AHN) is crucial for the maintenance of hippocampal function. Several neurodegenerative diseases such as Alzheimer's disease (AD) are accompanied by memory deficits that could be related to alterations in AHN. Here, we took advantage of a conditional mouse model to study the involvement of glycogen synthase kinase-3β (GSK-3β) overexpression (OE) in AHN. By injecting GFP- and PSD95-GFP-expressing retroviruses, we have determined that hippocampal GSK-3β-OE causes dramatic alterations in both dendritic tree morphology and post-synaptic densities in newborn neurons. Alterations in previously damaged neurons were reverted by switching off the transgenic system and also by using a physiological approach (environmental enrichment) to increase hippocampal plasticity. Furthermore, comparative morphometric analysis of granule neurons from patients with AD and from GSK-3β overexpressing mice revealed shared morphological alterations. Taken together, these data indicate that GSK-3β is crucial for hippocampal function, thereby supporting this kinase as a relevant target for the treatment of AD.

The development of animal embryos depends on accurate coordination of the growth and specification of precursor cells. Morphogens, extracellular signals that act at a distance to control cell fate, are crucial in the patterning of embryonic tissues. One of the most extensively studied examples of a morphogen patterned tissue is the developing vertebrate spinal cord. The distribution of distinct neuronal subtypes along the dorsoventral (DV) axis of the spinal cord is determined by counteracting gradients of long-range signals. Wnt and BMP signals promote dorsal identities, while Shh signaling induces ventral identities. Simultaneous to their specification, neural progenitors proliferate, facilitating the growth of the neural tube. In this review we discuss evidence indicating that the signals governing progenitor specification also control proliferation and survival of progenitor cells. Moreover, evidence of reciprocal transcriptional interactions and cross-talk between the signaling pathways has emerged from recent studies. Together these studies suggest ways in which patterning and growth may be coordinated in the spinal cord. One level of interaction is an inhibitory regulation of repressor forms of the transcription factor Gli3-generated in the absence of Shh-on b-catenin activity, the transcription factor activated by Wnt signaling. This interaction may also be relevant in other tissues and situations in which the two signaling pathways are known to participate.