Eph/Ephrin Signaling Controls Progenitor Identities In The Ventral Spinal Cord
Tóm tắt
In the vertebrate spinal cord, motor neurons (MN) are generated in stereotypical numbers from a pool of dedicated progenitors (pMN) whose number depends on signals that control their specification but also their proliferation and differentiation rates. Although the initial steps of pMN specification have been extensively studied, how pMN numbers are regulated over time is less well characterized. Here, we show that ephrinB2 and ephrinB3 are differentially expressed in progenitor domains in the ventral spinal cord with several Eph receptors more broadly expressed. Genetic loss-of-function analyses show that ephrinB2 and ephrinB3 inversely control pMN numbers and that these changes in progenitor numbers correlate with changes in motor neuron numbers. Detailed phenotypic analyses by immunostaining and genetic interaction studies between ephrinB2 and Shh indicate that changes in pMN numbers in ephrin mutants are due to alteration in progenitor identity at late stages of development. Altogether our data reveal that Eph:ephrin signaling is required to control progenitor identities in the ventral spinal cord.
Tài liệu tham khảo
Briscoe J, Novitch BG. Regulatory pathways linking progenitor patterning, cell fates and neurogenesis in the ventral neural tube. Philos Trans R Soc Lond B Biol Sci. 2008;363:57–70.
Dessaud E, McMahon AP, Briscoe J. Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network. Development. 2008;135:2489–503.
Dessaud E, et al. Interpretation of the sonic hedgehog morphogen gradient by a temporal adaptation mechanism. Nature. 2007;450(7170):717–20.
Dessaud E, et al. Dynamic assignment and maintenance of positional identity in the ventral neural tube by the morphogen sonic hedgehog. PLoS Biol. 2010;8(6):e1000382.
Balaskas N, et al. Gene regulatory logic for reading the Sonic Hedgehog signaling gradient in the vertebrate neural tube. Cell. 2012;148:273–84.
Cohen M, Briscoe J, Blassberg R. Morphogen interpretation: the transcriptional logic of neural tube patterning. Curr Opin Genet Dev. 2013;23(4):423–8.
Allen BL, Tenzen T, McMahon AP. The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev. 2007;21(10):1244–57.
Allen BL, et al. Overlapping roles and collective requirement for the coreceptors GAS1, CDO, and BOC in SHH pathway function. Dev Cell. 2011;20(6):775–87.
Kicheva A, et al. Coordination of progenitor specification and growth in mouse and chick spinal cord. Science. 2014;345(6204):1254927.
Wijgerde M, et al. A direct requirement for Hedgehog signaling for normal specification of all ventral progenitor domains in the presumptive mammalian spinal cord. Genes Dev. 2002;16:2849–64.
Lei Q, et al. Transduction of graded Hedgehog signaling by a combination of Gli2 and Gli3 activator functions in the developing spinal cord. Development. 2004;131:3593–604.
Wang H, et al. Tcf/Lef repressors differentially regulate Shh-Gli target gene activation thresholds to generate progenitor patterning in the developing CNS. Development. 2011;138:3711–21.
Xiong F, et al. Specified neural progenitors sort to form sharp domains after noisy Shh signaling. Cell. 2013;153:550–61.
Lisabeth EM, Falivelli G, Pasquale EB. Eph Receptor Signaling and Ephrins. Cold Spring Harb Perspect Biol. 2013;5:a009159.
Kania, A. and R. Klein, Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat Rev Mol Cell Biol. 2016;17:240–56.
Fagotto F, Winklbauer R, Rohani N. Ephrin-Eph signaling in embryonic tissue separation. Cell Adh Migr. 2014;8(4):308–26.
Cayuso, J., Q. Xu, and D.G. Wilkinson, Mechanisms of boundary formation by Eph receptor and ephrin signaling. Dev Biol. 2015;401:122–31.
Laussu J, et al. Beyond boundaries: Eph/ephrin signaling in neurogenesis. Cell Adh Migr. 2014;8:349–59.
Kao TJ, Kania A. Ephrin-mediated cis-attenuation of Eph receptor signaling is essential for spinal motor axon guidance. Neuron. 2011;71:76–91.
Luxey M, et al. Eph/ephrin-B1 forward signaling controls fasciculation of motor and sensory axons. Dev. Biol. 2013;383:264–74.
Luxey M, Laussu J, Davy A. EphrinB2 sharpens lateral motor column division in the developing spinal cord. Neural Dev. 2015;10:25.
Davy A, Soriano P. Ephrin-B2 forward signaling regulates somite patterning and neural crest cell development. Dev. Biol. 2007;304:182–93.
Grunwald IC, et al. Hippocampal plasticity requires postsynaptic ephrinBs. Nat. Neurosci. 2004;7:33–40.
Yokoyama N, et al. Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline. Neuron. 2001;29:85–97.
Schindelin J, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82.
Adams RH, et al. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 1998;13:295–306.
Wang HU, Chen Z-F, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor eph-B4. Cell. 1998;93:741–53.
Cau E, Blader P. Notch activity in the nervous system: to switch or not to switch? Neural Dev. 2009;4:36.
Helmbacher F, et al. Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development. 2000;127:3313–24.
Defourny J, et al. Cochlear supporting cell transdifferentiation and integration into hair cell layers by inhibition of ephrin-B2 signalling. Nat Commun. 2015;6:7017.
Picco V, Hudson C, Yasuo H. Ephrin-Eph signaliing drives the asymmetric division of notochord/neural precursors in Ciona embryos. Development. 2007;134:1491–7.
Stolfi A, et al. Neural tube patterning by Ephrin, FGF and Notch signaling relays. Development. 2011;138:5429–39.
Ashton RS, et al. Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling. Nat. Neurosci. 2012;15:1399–407.
Haupaix N, et al. p120RasGAP mediates ephrin/Eph-dependent attenuation of FGF/ERK signals during cell fate specification in ascidian embryos. Development. 2013;140:4347–52.
Ottone C, et al. Direct cell-cell contact with the vascular niche maintains quiescent neural stem cells. Nat Cell Biol. 2014;16(11):1045–56.
Chen S, et al. Interrogating cellular fate decisions with high-throughput arrays of multiplexed cellular communities. Nat Commun. 2016;7:10309.
Stasiulewicz, M., et al., A conserved role for Notch in priming the cellular response to Shh through ciliary localisation of the key Shh transducer, Smoothened. Development, 2015.
Kong JH, et al. Notch activity modulates the responsiveness of neural progenitors to sonic hedgehog signaling. Dev Cell. 2015;33(4):373–87.
Martinelli DC, Fan CM. Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev. 2007;21:1231–43.
Tenzen T, et al. The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell. 2006;10:647–56.