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RESEARCH PAPER

Targeted deletion of numb and numblike in sensory neurons reveals their essential functions in axon arborization

Departments of ¹ Pathology and ² Physiology and ³ Howard Hughes Medical Institute, University of California San Francisco, San Francisco, California 94143, USA; ⁴ Pathology Service, Veterans Administration Medical Center, San Francisco, California 94121, USA; ⁵ Departments of Psychiatry and Genetics, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02178, USA; ⁶ Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut 06520, USA

Mouse Numb homologs antagonize Notch1 signaling pathways through largely unknown mechanisms. Here we demonstrate that conditional mouse mutants with deletion of numb and numblike in developing sensory ganglia show a severe reduction in axonal arborization in afferent fibers, but no deficit in neurogenesis. Consistent with these results, expression of Cre recombinase in sensory neurons from numb conditional mutants results in reduced endocytosis, a significant increase in nuclear Notch1, and severe reductions in axon branch points and total axon length. Conversely, overexpression of Numb, but not mutant Numb lacking -adaptin-interacting domain, leads to accumulation of Notch1 in markedly enlarged endocytic–lysosomal vesicles, reduced nuclear Notch1, and dramatic increases in axonal length and branch points. Taken together, our data provide evidence for previously unidentified functions of Numb and Numblike in sensory axon arborization by regulating Notch1 via the endocytic–lysosomal pathways.

[Keywords: Numb; Numblike; Notch1; sensory neurons; axon arborization; endocytosis]

Received August 4, 2004; revised version accepted October 28, 2004.

Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1246005.

⁷ Corresponding author.

E-MAIL: ejhuang{at}itsa.ucsf.edu; FAX (415) 750-6947.

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