Netrin1 patterns the dorsal spinal cord through modulation of Bmp signaling

Sandy Alvarez; Sandeep Gupta; Yesica Mercado-Ayon; Kaitlyn Honeychurch; Cristian Rodriguez; Riki Kawaguchi; Samantha J Butler

doi:10.1016/j.celrep.2024.114954

Netrin1 patterns the dorsal spinal cord through modulation of Bmp signaling

Cell Rep. 2024 Nov 7:114954. doi: 10.1016/j.celrep.2024.114954. Online ahead of print.

Authors

Sandy Alvarez¹, Sandeep Gupta², Yesica Mercado-Ayon¹, Kaitlyn Honeychurch², Cristian Rodriguez³, Riki Kawaguchi⁴, Samantha J Butler⁵

Affiliations

¹ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; CIRM Bridges to Research Program, California State University, Northridge, CA 91330, USA.
⁴ Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual & Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].

PMID: 39547237
DOI: 10.1016/j.celrep.2024.114954

Abstract

We have identified an unexpected role for netrin1, a canonical axonal guidance cue, as a suppressor of bone morphogenetic protein (Bmp) signaling in the developing dorsal spinal cord. Using a combination of gain- and loss-of-function approaches in chicken and mouse embryonic models, as well as mouse embryonic stem cells (mESCs), we have observed that manipulating the level of netrin1 specifically alters the patterning of the Bmp-dependent dorsal interneurons (dIs), dI1-dI3. Altered netrin1 levels also change Bmp signaling activity, as assessed using bioinformatic approaches, as well as monitoring phosophoSmad1/5/8 activation, the canonical intermediate of Bmp signaling, and Id levels, a known Bmp target. Together, these studies support the hypothesis that netrin1 acts from the intermediate spinal cord to regionally confine Bmp signaling to the dorsal spinal cord. Thus, netrin1 has reiterative activities shaping dorsal spinal circuits, first by regulating cell fate decisions and then acting as a guidance cue to direct axon extension.

Keywords: Bmp; Bmp inhibition; CP: Developmental biology; CP: Neuroscience; cell fate; dorsal interneurons; interneuron differentiation; netrin1; neural development; patterning; spinal cord.