Shh-mediated centrosomal recruitment of PKA promotes symmetric proliferative neuroepithelial cell division

Tight control of the balance between self-expanding symmetric and self-renewing asymmetric neural progenitor divisions is crucial to regulate the number of cells in the developing central nervous system. We recently demonstrated that Sonic hedgehog (Shh) signalling is required for the expansion of motor neuron progenitors by maintaining symmetric divisions. Here we show that activation of Shh/Gli signalling in dividing neuroepithelial cells controls the symmetric recruitment of PKA to the centrosomes that nucleate the mitotic spindle, maintaining symmetric proliferative divisions. Notably, Shh signalling upregulates the expression of pericentrin, which is required to dock PKA to the centrosomes, which in turn exerts a positive feedback onto Shh signalling. Thus, by controlling centrosomal protein assembly, we propose that Shh signalling overcomes the intrinsic asymmetry at the centrosome during neuroepithelial cell division, thereby promoting self-expanding symmetric divisions and the expansion of the progenitor pool.The work in E.M.’s laboratory was supported by grants BFU2013-46477-P and BFU2014-55738-REDT.Peer reviewe

Delamination of neural crest cells requires transient and reversible Wnt inhibition mediated by Dact1/2

Delamination of neural crest (NC) cells is a bona fide physiological model of epithelial-to-mesenchymal transition (EMT), a process that is influenced by Wnt/β-catenin signalling. Using two in vivo models, we show that Wnt/β-catenin signalling is transiently inhibited at the time of NC delamination. In attempting to define the mechanism underlying this inhibition, we found that the scaffold proteins Dact1 and Dact2, which are expressed in pre-migratory NC cells, are required for NC delamination in Xenopus and chick embryos, whereas they do not affect the motile properties of migratory NC cells. Dact1/2 inhibit Wnt/β-catenin signalling upstream of the transcriptional activity of T cell factor (TCF), which is required for EMT to proceed. Dact1/2 regulate the subcellular distribution of β-catenin, preventing β-catenin from acting as a transcriptional coactivator to TCF, yet without affecting its stability. Together, these data identify a novel yet important regulatory element that inhibits β-catenin signalling, which then affects NC delamination.This work was supported by the Medical Research Council [MR/J000655/1 and MR/ M010465 to R.M.]; the Biotechnology and Biological Sciences Research Council (BBSRC) [M008517 to R.M.]; the Ministerio de Economı́a y Competitividad [BFU2011-24099 to S.P.; BFU2013-46477-P and BFU2014-55738-REDT to E.M.].Peer Reviewe

Cell intercalation driven by SMAD3 underlies secondary neural tube formation

Body axis elongation is a hallmark of the vertebrate embryo, involving the architectural remodeling of the tail bud. Although it is clear how neuromesodermal progenitors (NMPs) contribute to embryo elongation, the dynamic events that lead to de novo lumen formation and that culminate in the formation of a 3-dimensional, neural tube from NMPs, are poorly understood. Here, we used in vivo imaging of the chicken embryo to show that cell intercalation downstream of TGF-β/SMAD3 signaling is required for secondary neural tube formation. Our analysis describes the events in embryo elongation including lineage restriction, the epithelial-to-mesenchymal transition of NMPs, and the initiation of lumen formation. We show that the resolution of a single, centrally positioned lumen, which occurs through the intercalation of central cells, requires SMAD3/Yes-associated protein (YAP) activity. We anticipate that these findings will be relevant to understand caudal, skin-covered neural tube defects, among the most frequent birth defects detected in humans.The work in EM’s laboratory was supported by grants BFU2016-77498-P and RED2018-102553-T. EGG was recipient of a BES-2014-068589 PhD scholarship. JBA is a recipient of a BES-2017-080050 PhD scholarship

E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner

Class II HLH proteins heterodimerize with class I HLH/E proteins to regulate transcription. Here, we show that E proteins sharpen neurogenesis by adjusting the neurogenic strength of the distinct proneural proteins. We find that inhibiting BMP signaling or its target ID2 in the chick embryo spinal cord, impairs the neuronal production from progenitors expressing ATOH1/ASCL1, but less severely that from progenitors expressing NEUROG1/2/PTF1a. We show this context-dependent response to result from the differential modulation of proneural proteins’ activity by E proteins. E proteins synergize with proneural proteins when acting on CAGSTG motifs, thereby facilitating the activity of ASCL1/ATOH1 which preferentially bind to such motifs. Conversely, E proteins restrict the neurogenic strength of NEUROG1/2 by directly inhibiting their preferential binding to CADATG motifs. Since we find this mechanism to be conserved in corticogenesis, we propose this differential co-operation of E proteins with proneural proteins as a novel though general feature of their mechanism of action.Asociación Española Contra el Cáncer AIO2014 Gwenvael Le Dreau Consejo Nacional de Ciencia y Tecnologı´a Rene´ Escalona Ministerio de Educación, Cultura y Deporte #FPU13/01384 Raquel Fueyo Ministerio de Economía y Competitividad #FJCI-2015-26175 Antonio Herrera Ministerio de Economía y Competitividad BFU2014-53633-P Sebastian Pons Ministerio de Economı´a y Competitividad BFU2015-69248-P Marian A Martinez-Balbas Fondation Jerome Lejeune Fondation Jerome Lejeune.2016 Marian A Martinez-Balbas Ministerio de Economía y Competitividad BFU2016-81887-REDT Elisa Marti Ministerio de Economía y Competitividad BFU2016-77498-P Elisa MartiPeer reviewe