Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice

Loss of brain-derived neurotrophic factor-dependent neural crest-derived sensory neurons in neurotrophin-4 mutant mice

^*Center for Developmental Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75235-9133; and ^†Neural Development Group, ABL-Basic Research Program, Frederick Cancer Research and Development Center, Frederick, MD 21702

Communicated by Joseph L. Goldstein, University of Texas Southwestern Medical Center, Dallas, TX (received for review December 1, 1999)

Abstract

Peripheral ganglion neurons confer sensory information including touch, pain, temperature, and proprioception. Sensory modality is linked to specific neurotrophin (NTF) requirements. NT-3 supports survival of neurons that differentiate primarily into proprioceptors whereas nerve growth factor and brain-derived neurotrophic factor (BDNF) support subpopulations that transmit nociception and mechanoreception, respectively. We examined sensory neurons of gene-targeted mouse mutants at the NT-4, BDNF, NT-3, and TrkA loci. We show that NT-4 functions early in gangliogenesis, upstream of BDNF. In the absence of NT-4 function, BDNF-dependent, TrkB-expressing neurons fail to appear. The results are consistent with the model that precursor cells intended to become BDNF-dependent mechanoreceptors instead differentiate into NT-3-dependent proprioceptive neurons.

Footnotes

↵ ‡ To whom reprint requests should be addressed. E-mail: parada{at}utsw.swmed.edu.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.040562597.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.040562597
Abbreviations:

NTF,

neurotrophin;

NT-3 and NT-4,

neurotrophin-3 and -4, respectively;

BDNF,

brain-derived neurotrophic factor;

NGF,

nerve growth factor;

E,

embryonic day;

DRG,

dorsal root ganglion;

wt,

wild type;

H&E,

hematoxylin/eosin;

TdT,

terminal deoxynucleotidyltransferase;

TUNEL,

TdT-mediated dUTP-biotin nick end labeling