ALK5-dependent TGF-β signaling is a major determinant of late-stage adult neurogenesis

Yingbo He; Hui Zhang; Andrea Yung; Saul A Villeda; Philipp A Jaeger; Oluwatobi Olayiwola; Nina Fainberg; Tony Wyss-Coray

doi:10.1038/nn.3732

ALK5-dependent TGF-β signaling is a major determinant of late-stage adult neurogenesis

Nat Neurosci. 2014 Jul;17(7):943-52. doi: 10.1038/nn.3732. Epub 2014 May 25.

Authors

Yingbo He¹, Hui Zhang¹, Andrea Yung², Saul A Villeda³, Philipp A Jaeger³, Oluwatobi Olayiwola¹, Nina Fainberg¹, Tony Wyss-Coray⁴

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
² Department of Biology, Stanford University, Stanford, California, USA.
³ Present address: The Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA (S.A.V.), Department of Bioengineering, University of California San Diego, La Jolla, California, USA, and Department of Medicine, University of California San Diego, La Jolla, California, USA (P.A.J.).
⁴ 1] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA. [2] Center for Tissue Regeneration, Repair and Rehabilitation, VA Palo Alto Health Care System, Palo Alto, California, USA.

PMID: 24859199
PMCID: PMC4096284
DOI: 10.1038/nn.3732

Abstract

The transforming growth factor-β (TGF-β) signaling pathway serves critical functions in CNS development, but, apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β signaling in adult neurogenesis, genetic deletion of the TGF-β receptor ALK5 reduced the number, migration and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a marked increase in these aspects of neurogenesis and was associated with higher expression of c-Fos in newborn neurons and with stronger memory function. Our findings describe an unexpected role for ALK5-dependent TGF-β signaling as a regulator of the late stages of adult hippocampal neurogenesis, which may have implications for changes in neurogenesis during aging and disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Animals, Newborn
Blotting, Western
Conditioning, Psychological
Dentate Gyrus / physiology
Dependovirus
Doxycycline / pharmacology
Fear / psychology
Female
Gene Expression / physiology
Genetic Vectors
Hippocampus / growth & development*
Hippocampus / physiology
Immunohistochemistry
Luciferases / genetics
Male
Memory / physiology
Mice
Mice, Inbred C57BL
Microarray Analysis
Microscopy, Confocal
Neurogenesis / physiology*
Neurons / physiology
Protein Serine-Threonine Kinases / physiology*
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / physiology*
Signal Transduction / physiology*
Stereotaxic Techniques
Transforming Growth Factor beta / physiology*

Substances

Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta
Luciferases
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I
Tgfbr1 protein, mouse
Doxycycline

Associated data

GEO/GSE53761

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding