The Cerebellum

, Volume 7, Issue 3, pp 451–466

Both Cell-Autonomous and Cell Non-Autonomous Functions of GAP-43 are Required for Normal Patterning of the Cerebellum In Vivo

  • Yiping Shen
  • Rashmi Mishra
  • Shyamala Mani
  • Karina F. Meiri
Article

DOI: 10.1007/s12311-008-0049-5

Cite this article as:
Shen, Y., Mishra, R., Mani, S. et al. Cerebellum (2008) 7: 451. doi:10.1007/s12311-008-0049-5

Abstract

Growth-associated protein 43 (GAP-43) is required for development of a functional cerebral cortex in vertebrates; however, its role in cerebellar development is not well understood. Recently, we showed that absence of GAP-43 caused defects in proliferation, differentiation, and polarization of cerebellar granule cells. In this paper, we show that absence of GAP-43 causes defects in cerebellar patterning that reflect both cell-autonomous and non-autonomous functions. Cell-autonomous effects of GAP-43 impact precursor proliferation and axon targeting: In its absence, (1) proliferation of granule cell precursors in response to sonic hedgehog and fibroblast growth factor is inhibited, (2) proliferation of neuroepithelial precursors is inhibited, and (3) targeting of climbing fibers to the central lobe is disrupted. Cell non-autonomous effects of GAP-43 impact differentiated Purkinje cells in which GAP-43 has been downregulated: In its absence, both maturation and mediolateral patterning of Purkinje cells are inhibited. Both cell-autonomous and non-autonomous functions of GAP-43 involve its phosphorylation by protein kinase C. GAP-43 is phosphorylated in granule cell precursors in response to sonic hedgehog in vitro, and phosphorylated GAP-43 is also found in proliferating neuroepithelium and climbing fibers. Phosphorylated GAP-43 is specifically enriched in the presynaptic terminals of parallel and climbing fibers that innervate Purkinje cell bodies and dendrites. The cell-autonomous and non-autonomous effects of GAP-43 converge on the central lobe. The multiple effects of GAP-43 on cerebellar development suggest that it is a critical downstream transducer of signaling mechanisms that integrate generation of cerebellar structure with functional parcellation at the central lobe.

Keywords

GAP-43Knockout mouseCerebellar granule cell proliferationPurkinje cell patterningSonic hedgehogClimbing fibers

Abbreviations

ABT

anterobasal tract

ADT

anterodorsal tract

AL

anterior lobe

BrDU

bromodeoxyuridine

CeL

central lobe

CeT

central tract

CF

climbing fiber

Cp

cerebellar peduncle

EGL

external granule cell layer

FGF

fibroblast growth factor

FN

fastigial nucleus

GAP-43

growth-associated protein 43

GC

granule cell

GCP

granule cell precursor

IgSFCAM

immunoglobulin superfamily cell adhesion molecule

LI

labeling index

ML

molecular layer

NCAM

neural cell adhesion molecule

PC

Purkinje cell

PCP

Purkinje cell precursor

PKC

protein kinase C

PL

posterior lobe

Ptc-1

patched-1

POT

posterior tract

Shh

sonic hedgehog

Smo

smoothened

SVZ

subventricular zone

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Yiping Shen
    • 1
  • Rashmi Mishra
    • 2
  • Shyamala Mani
    • 2
  • Karina F. Meiri
    • 1
  1. 1.Department of Anatomy and Cellular BiologyTufts University School of MedicineBostonUSA
  2. 2.National Brain Research CenterManesarIndia