Slit‐Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain

Ricaño-Cornejo, Itzel; Altick, Amy L.; García-Peña, Claudia M.; Nural, Hikmet; Echevarrı́a, Diego; Miquelajáuregui, Amaya; Mastick, Grant S.; Varela‐Echavarría, Alfredo

doi:10.1002/jnr.22684

Cited by 16 publications

(26 citation statements)

References 47 publications

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“…Robo2 and Slit1 were expressed in the mouse developing hypothalamus from E10.5 and were required to maintain proper balance between primary and intermediate neuronal progenitors [27]. This function was probably conserved in the chick.…”

Section: Discussionmentioning

confidence: 99%

Novel genes upregulated when NOTCH signalling is disrupted during hypothalamic development

et al. 2013

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BackgroundThe generation of diverse neuronal types and subtypes from multipotent progenitors during development is crucial for assembling functional neural circuits in the adult central nervous system. It is well known that the Notch signalling pathway through the inhibition of proneural genes is a key regulator of neurogenesis in the vertebrate central nervous system. However, the role of Notch during hypothalamus formation along with its downstream effectors remains poorly defined.ResultsHere, we have transiently blocked Notch activity in chick embryos and used global gene expression analysis to provide evidence that Notch signalling modulates the generation of neurons in the early developing hypothalamus by lateral inhibition. Most importantly, we have taken advantage of this model to identify novel targets of Notch signalling, such as Tagln3 and Chga, which were expressed in hypothalamic neuronal nuclei.ConclusionsThese data give essential advances into the early generation of neurons in the hypothalamus. We demonstrate that inhibition of Notch signalling during early development of the hypothalamus enhances expression of several new markers. These genes must be considered as important new targets of the Notch/proneural network.

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Section: Discussionmentioning

confidence: 99%

Novel genes upregulated when NOTCH signalling is disrupted during hypothalamic development

et al. 2013

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“…In line with our observations, it has been shown that FGFRs regulate axon guidance cues such as slit and semaphorin3A to control axonal pathfinding 46,49 . Slit-Robo signals regulate the pathfinding of multiple axonal pathways, including corticofugal, thalamocortical, and callosal connection [68][69][70][71] . Frizzled-3, one of the members in Wnt-Frizzled pathway, is required for the development of multiple axon tracts including anterior commissure, corticofugal axons, thalamocortical axons, and corpus callosum in the mouse CNS [72][73][74][75] .…”

Section: Fgfr3 Gof In Nex-lineage Neurons Leads Miswiring Of Several mentioning

confidence: 99%

Enhanced FGFR3 activity in post-mitotic principal neurons during brain development results in cortical dysplasia and axon miswiring

Huang

Krebs

Miskus

et al. 2020

Preprint

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Abnormal levels of fibroblast growth factors (FGFs) and FGF receptors (FGFRs) have been detected in various neurological disorders. The potent impact of FGF-FGFR in multiple embryonic developmental processes makes it challenging to elucidate their roles in post-mitotic neurons. Taking an alternative approach, we directly examined the impact of aberrant FGFR function after neurogenesis by generating a FGFR gain-of-function (GOF) transgenic mouse which expresses constitutively activated FGFR3 (FGFR3 K650E ) in post-mitotic glutamatergic neurons. We found that enhanced FGFR activity in glutamatergic neurons results in abnormal radial migration and axonal miswiring. Regarding the lamination phenotype in GOF brains, we found later-born Cux1-positive neurons are dispersed throughout the GOF cortex. Such a cortical migration deficit is likely caused, at least in part, by a significant reduction of the radial processes normally projecting from the radial glia cells (RGCs). In addition, FGFR3 GOF also results in the misrouting of several long-range axonal projections, including the corpus callosum, anterior commissure, and postcommissural fornix. RNA-sequencing analysis of the GOF embryonic cortex reveals significant alterations in several pathways involved in cell cycle regulation and axonal pathfinding. Collectively, our results suggest that FGFR hyperfunction in post-mitotic neurons at the late embryonic stage result in cortical dysplasia and circuit miswiring.

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“…S4). Robo-Slit signaling regulates the guidance of longitudinally projecting axons in the developing mouse brain stem (Dugan et al, 2011;Farmer et al, 2008;Mastick et al, 2010), forebrain (Devine and Key, 2008;Ricano-Cornejo et al, 2011) and spinal cord (Reeber et al, 2008 (Brose et al, 1999;Kadison et al, 2006;Yuan et al, 1999) might play a key role in constraining the orientation of longitudinally projecting SACMN axons as Slit1 and Slit2 position retinal ganglion cell axons at the optic chiasm (Plump et al, 2002).…”

Section: Nkx29 Regulates Robo2 Expressionmentioning

confidence: 99%

Motor axon exit from the mammalian spinal cord is controlled by the homeodomain protein Nkx2.9 via Robo-Slit signaling

2012

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SUMMARYMammalian motor circuits control voluntary movements by transmitting signals from the central nervous system (CNS) to muscle targets. To form these circuits, motor neurons (MNs) must extend their axons out of the CNS. Although exit from the CNS is an indispensable phase of motor axon pathfinding, the underlying molecular mechanisms remain obscure. Here, we present the first identification of a genetic pathway that regulates motor axon exit from the vertebrate spinal cord, utilizing spinal accessory motor neurons (SACMNs) as a model system. SACMNs are a homogeneous population of spinal MNs with axons that leave the CNS through a discrete lateral exit point (LEP) and can be visualized by the expression of the cell surface protein BEN. We show that the homeodomain transcription factor Nkx2.9 is selectively required for SACMN axon exit and identify the Robo2 guidance receptor as a likely downstream effector of Nkx2.9; loss of Nkx2.9 leads to a reduction in Robo2 mRNA and protein within SACMNs and SACMN axons fail to exit the spinal cord in Robo2-deficient mice. Consistent with short-range interactions between Robo2 and Slit ligands regulating SACMN axon exit, Robo2-expressing SACMN axons normally navigate through LEP-associated Slits as they emerge from the spinal cord, and fail to exit in Slit-deficient mice. Our studies support the view that Nkx2.9 controls SACMN axon exit from the mammalian spinal cord by regulating Robo-Slit signaling.

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Slit‐Robo signals regulate pioneer axon pathfinding of the tract of the postoptic commissure in the mammalian forebrain

Cited by 16 publications

References 47 publications

Novel genes upregulated when NOTCH signalling is disrupted during hypothalamic development

Novel genes upregulated when NOTCH signalling is disrupted during hypothalamic development

Enhanced FGFR3 activity in post-mitotic principal neurons during brain development results in cortical dysplasia and axon miswiring

Motor axon exit from the mammalian spinal cord is controlled by the homeodomain protein Nkx2.9 via Robo-Slit signaling

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