Complex crosstalk of Notch and Hedgehog signalling during the development of the central nervous system
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Cellular and Molecular Life Sciences
REVIEW
Complex crosstalk of Notch and Hedgehog signalling during the development of the central nervous system Craig T. Jacobs1 · Peng Huang1 Received: 15 April 2020 / Revised: 23 June 2020 / Accepted: 20 August 2020 © Springer Nature Switzerland AG 2020
Abstract The development of the vertebrate central nervous system (CNS) is tightly regulated by many highly conserved cell signalling pathways. These pathways ensure that differentiation and migration events occur in a specific and spatiotemporally restricted manner. Two of these pathways, Notch and Hedgehog (Hh) signalling, have been shown to form a complex web of interaction throughout different stages of CNS development. Strikingly, some processes employ Notch signalling to regulate Hh response, while others utilise Hh signalling to modulate Notch response. Notch signalling functions upstream of Hh response through controlling the trafficking of integral pathway components as well as through modulating protein levels and transcription of downstream transcriptional factors. In contrast, Hh signalling regulates Notch response by either indirectly controlling expression of key Notch ligands and regulatory proteins or directly through transcriptional control of canonical Notch target genes. Here, we review these interactions and demonstrate the level of interconnectivity between the pathways, highlighting context-dependent modes of crosstalk. Since many other developmental signalling pathways are active in these tissues, it is likely that the interplay between Notch and Hh signalling is not only an example of signalling crosstalk but also functions as a component of a wider, multi-pathway signalling network. Keywords Notch signalling · Hedgehog signalling · Spinal cord · Central nervous system · Crosstalk
Introduction The mature vertebrate central nervous system (CNS) consists of many distinct classes of neurons throughout the brain, spinal cord and retina. Each individual structure of the CNS is composed of a plethora of unique cell types organised in a specific spatiotemporal pattern that arises from a sheet of equivalent neural progenitor cells (NPCs), known as the neural plate, during development [1]. This pattern formation occurs in three-dimensional space, as highlighted by the layered structure of the spinal cord and cortex, demonstrating a requirement for local communication. In order to create functional neural networks, specific cell types must form within this three-dimensional space in distinct time windows. This occurs through selective temporal interactions * Peng Huang [email protected] 1
between cells, providing a critical fourth dimension of control in the complex patterning of the CNS [2]. Understanding how these interactions are mediated is crucial in understanding how one of the most complex and important systems in the body is formed. Due to the delicate balance of control, when problems arise during CNS development, the resulting phenotypes are highly variable. Minor inaccuracies can cause anyth
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