Enhanced Neuronal Regeneration in the CAST/Ei Mouse Strain Is Linked to Expression of Differentiation Markers after Injury
Véronique Lisi,
Bhagat Singh,
Michel Giroux,
Elmer Guzman,
Michio W. Painter,
Yung-Chih Cheng,
Eric Huebner,
Giovanni Coppola,
Michael Costigan,
Clifford J. Woolf,
Kenneth S. Kosik
Affiliations
Véronique Lisi
Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
Bhagat Singh
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Michel Giroux
Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
Elmer Guzman
Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA
Michio W. Painter
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Yung-Chih Cheng
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Eric Huebner
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Giovanni Coppola
Departments of Psychiatry and Neurology, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Michael Costigan
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA; Anaesthesia Department, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Clifford J. Woolf
F.M. Kirby Neurobiology Center, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
Kenneth S. Kosik
Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA; Corresponding author
Summary: Peripheral nerve regeneration after injury requires a broad program of transcriptional changes. We investigated the basis for the enhanced nerve regenerative capacity of the CAST/Ei mouse strain relative to C57BL/6 mice. RNA sequencing of dorsal root ganglia (DRG) showed a CAST/Ei-specific upregulation of Ascl1 after injury. Ascl1 overexpression in DRG neurons of C57BL/6 mice enhanced their neurite outgrowth. Ascl1 is regulated by miR-7048-3p, which is downregulated in CAST/Ei mice. Inhibition of miR-7048-3p enhances neurite outgrowth. Following injury, CAST/Ei neurons largely retained their mature neuronal profile as determined by single-cell RNA- seq, whereas the C57BL/6 neurons acquired an immature profile. These findings suggest that one facet of the enhanced regenerative phenotype is preservation of neuronal identity in response to injury. : Lisi et al. find that increased Ascl1 expression is associated with the superior regenerative capacity of CAST/Ei mice. Single-cell RNA-seq demonstrated that CAST/Ei mice retained more mature neurons after injury than did C57BL/6 mice, thereby suggesting that genetic drivers of the enhanced regenerative phenotype include mechanisms to preserve neuronal identity after injury. Keywords: single-cell analyses, RNA sequencing, regeneration, dorsal root ganglia, CAST/Ei, Ascl1, miR-7048
