A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development

Soskis, Michael J.; Ho, Hsin‐Yi Henry; Bloodgood, Brenda L.; Robichaux, Michael A.; Malik, Athar N.; Ataman, Bulent; Rubin, Alex A.; Zieg, Janine; Zhang, Chao; Shokat, Kevan M.; Sharma, Nikhil; Cowan, Christopher W.; Greenberg, Michael E.

doi:10.1038/nn.3249

Cited by 36 publications

(37 citation statements)

References 53 publications

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“…The gene encoding ephrin receptor B1 (Ephb1) is critical for axon guidance and synaptogenesis in the brain (68). The Ubr3 gene encodes a ubiquitin protein ligase E3 component that has been shown to be necessary for olfaction of neonatal mice (69).…”

Section: Methodsmentioning

confidence: 99%

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

Cui¹,

Ding²,

Shu³

et al. 2016

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 99%

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

Cui¹,

Ding²,

Shu³

et al. 2016

Journal of Clinical Investigation

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“…All EphB mutant mice were previously described (23)(24)(25)44). EphrinB1 loxp and EphrinB2 loxp cKO mice were previously described (32,45).…”

Section: Methodsmentioning

confidence: 99%

“…We next analyzed an analog-sensitive EphB receptor KI mouse (AS-EphB) that possesses point mutations within the conserved intracellular kinase domain that renders the endogenous EphB1-3 receptors sensitive to the reversible kinase inhibitor, 1-NA-PP1, in vivo (25). Twice daily injections of vehicle or 1-NA-PP1 (80 mg/kg) to timed-pregnant AS-EphB mutant (or WT control) mice from E12.5 to E19.0 resulted in significant VTel axon guidance errors, including severe ventral misprojections (Fig.…”

Section: Ephb1 and Ephb2mentioning

confidence: 99%

EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding

Robichaux

Chenaux

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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In early brain development, ascending thalamocortical axons (TCAs) navigate through the ventral telencephalon (VTel) to reach their target regions in the young cerebral cortex. Descending, deep-layer cortical axons subsequently target appropriate thalamic and subcortical target regions. However, precisely how and when corticothalamic axons (CTAs) identify their appropriate, reciprocal thalamic targets remains unclear. We show here that EphB1 and EphB2 receptors control proper navigation of a subset of TCA and CTA projections through the VTel. We show in vivo that EphB receptor forward signaling and the ephrinB1 ligand are required during the early navigation of L1-CAM + thalamic fibers in the VTel, and that the misguided thalamic fibers in EphB1/2 KO mice appear to interact with cortical subregion-specific axon populations during reciprocal cortical axon guidance. As such, our findings suggest that descending cortical axons identify specific TCA subpopulations in the dorsal VTel to coordinate reciprocal corticalthalamic connectivity in the early developing brain.

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“…EphA4 is a receptor tyrosine kinase involved in neuronal development and axon guidance in mammals 17,18 and has recently been identified as a potential therapeutic target for the treatment of amyotrophic lateral sclerosis (ALS) 17,19 . EphA4 belongs to the ephrin (Eph) receptor family of 16 tyrosine kinases, a branch of the kinome that is inherently sensitive to the PP inhibitor scaffold.…”

Section: Resultsmentioning

confidence: 99%

Staurosporine-Derived Inhibitors Broaden the Scope of Analog-Sensitive Kinase Technology

et al. 2013

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Analog-sensitive (AS) kinase technology is a powerful approach for studying phospho-signaling pathways in diverse organisms and physiological processes. The key feature of this technique is that a kinase-of-interest can be mutated to sensitize it to inhibitor analogs that do not target wild-type (WT) kinases. In theory, this enables specific inhibition of any kinase in cells and in mouse models of human disease. Typically these inhibitors are identified from a small library of molecules based on the pyrazolopyrimidine (PP) scaffold. However, we recently identified a subset of native human kinases, including the Ephrin A kinase family, that are sensitive to commonly used PP inhibitors. In an effort to develop a bioorthogonal AS-kinase inhibitor and to extend this technique to PP-sensitive kinases we sought an alternative inhibitor scaffold. Here we report the structure-based design of synthetically tractable, potent, and extremely selective AS-kinase inhibitors based on the natural product staurosporine. We demonstrate that these molecules, termed staralogs, potently target AS kinases in cells and we employ X-ray crystallography to elucidate their mechanism of efficacy. Finally, we demonstrate that staralogs target AS mutants of PP-sensitive kinases at concentrations where there is little to no inhibition of native human kinases. Thus, staralogs represent a new class of AS-kinase inhibitors and a core component of the chemical genetic tool kit for probing kinase-signaling pathways.

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A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development

Cited by 36 publications

References 53 publications

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity

EphB receptor forward signaling regulates area-specific reciprocal thalamic and cortical axon pathfinding

Staurosporine-Derived Inhibitors Broaden the Scope of Analog-Sensitive Kinase Technology

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