Ndfip1 is required for the development of pyramidal neuron dendrites and spines in the neocortex

Vicki E Hammond; Jenny M Gunnersen; Choo-Peng Goh; Ley-Hian Low; Tomoko Hyakumura; Michelle M Tang; Joanne M Britto; Ulrich Putz; Jason A Howitt; Seong-Seng Tan

doi:10.1093/cercor/bht191

Ndfip1 is required for the development of pyramidal neuron dendrites and spines in the neocortex

Cereb Cortex. 2014 Dec;24(12):3289-300. doi: 10.1093/cercor/bht191. Epub 2013 Jul 29.

Affiliations

¹ Florey Institute of Neuroscience and Mental Health and.
² Florey Institute of Neuroscience and Mental Health and Department of Anatomy and Neuroscience, The University of Melbourne, Victoria 3010, Australia.

PMID: 23897647
DOI: 10.1093/cercor/bht191

Abstract

Ubiquitin ligases of the Nedd4 family are important for axon and dendrite development, but little is known about their adaptor, Nedd4 family-interacting protein 1 (Ndfip1), that is responsible for their enzymatic activation. To study the function of Ndfip1 in cortical development, we generated a conditional knock-out (conditional KO) in neurons. The Ndfip1 conditional KO mice were viable; however, cortical neurons in the adult brain exhibited atrophic characteristics, including stunted dendritic arbors, blebbing of dendrites, and fewer dendritic spines. In electron micrographs, these neurons appeared shrunken with compacted somata and involutions of the nuclear membrane. In culture, Ndfip1 KO neurons exhibited exuberant sprouting suggesting loss of developmental control. Biochemical analysis of postsynaptic density (PSD) fractions from Ndfip1 KO cortical and hippocampal neurons showed that the postsynaptic proteins (Arc and PSD-95) were reduced compared with wild-type controls. In addition, the PI3 kinase/Akt signaling pathway was altered. These results indicate that Ndfip1, through its Nedd4 effectors, is important for the development of dendrites and dendritic spines in the cortex.

Keywords: Nedd4; dendrites; development; spines; ubiquitin ligase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Carrier Proteins / genetics*
Cell Fractionation
Cells, Cultured
Dendritic Spines / metabolism*
Disks Large Homolog 4 Protein
Embryo, Mammalian
Gene Expression Regulation, Developmental / genetics
Gene Expression Regulation, Developmental / physiology*
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Guanylate Kinases / metabolism
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Intercellular Signaling Peptides and Proteins
Membrane Proteins / deficiency
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neocortex* / cytology
Neocortex* / embryology
Neocortex* / growth & development
Nestin / genetics
Nestin / metabolism
PTEN Phosphohydrolase / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Pyramidal Cells / diagnostic imaging*
Transcription Factors / genetics
Transcription Factors / metabolism
Transfection
Ultrasonography

Substances

Carrier Proteins
Disks Large Homolog 4 Protein
Dlg4 protein, mouse
Homeodomain Proteins
Intercellular Signaling Peptides and Proteins
Membrane Proteins
Ndfip1 protein, mouse
Nestin
Transcription Factors
empty spiracles homeobox proteins
enhanced green fluorescent protein
Green Fluorescent Proteins
Proto-Oncogene Proteins c-akt
Guanylate Kinases
PTEN Phosphohydrolase