Absence of Sensory Neurons before Target Innervation in Brain-Derived Neurotrophic Factor-, Neurotrophin 3-, and TrkC-Deficient Embryonic Mice

Abstract

Gene-targeting experiments of Trk receptors and neurotrophins has confirmed the expectation that embryonic sensory and sympathetic neurons require neurotrophin function for survival. They have further revealed correlation between a specific neurotrophin requirement and eventual sensory modality. We have analyzed embryonic and neonatal mice with mutations in the BDNF, neurotrophin 3 (NT-3), and TrkC genes. Our data confirm an unexpectedly high proportion of sensory neuron losses in NT-3 (>70%), BDNF (>20%), and TrkC (>30%) mutants, which encompass populations thought to be NGF-dependent. Direct comparison of TrkC and NT-3 mutants indicates that only a subset of the NT-3-dependent neurons also requires TrkC. The observed losses in our TrkC mutant, which is null for all proteins encoded by the gene, are more severe than those previously reported for the kinase-negative TrkC mutation, implicating additional and important functions for the truncated receptors. Our data further indicate that mature NGF-requiring neurons undergo precocious and transitory requirements for NT-3 and/or BDNF. We suggest that neurotrophins may function in creating early heterogeneity that would enable ganglia to compensate for diverse modality requirements before the period of naturally occurring death.

Lack of the endosomal SNAREs vti1a and vti1b led to significant impairments in neuronal development

“…E12.5 DKO DRGs were already smaller, indicating that the onset of the phenotype is too early for neurite outgrowth as only cause. Cell loss in DRGs starts at E11 in the absence of local NT-3 before target innervation between E13 and E16 (45).…”

Combinatorial Therapy with Neurotrophins and cAMP Promotes Axonal Regeneration beyond Sites of Spinal Cord Injury

“…Previously, this system has exhibited sensitivity to cAMP administration (Neumann et al, 2002;Qiu et al, 2002) and to neurotrophin-3 (NT-3) (ElShamy and Ernfors, 1996;Liebl et al, 1997;Bradbury et al, 1999;Lu et al, 2003). Sixty adult female F344 rats were divided into five experimental groups (Table 1).…”

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…Survival and proliferation of cortical astrocytes (Sibilia et al 1998;Wagner et al 2006); Astrocyte development and neuronal survival (Kornblum et al 1998 Regulation of neural tube development (Deng et al 1997;Hasegawa et al 2004); OL differentiation (Zhou et al 2006) p75NTR Negative regulation of hippocampal pyramidal neuron dendritic morphology and neurite outgrowth (Zagrebelsky et al 2005); Schwann cell migration, remyelination (Bentley and Lee 2000;Song et al 2006;Tomita et al 2007) TrkA Development of sensory sympathetic and cholinergic neurons Fagan et al 1996) TrkB Development of motor and/or sensory neurons (Ernfors et al 1994;Klein 1994;Pinon et al 1996); Interneuron migration (Polleux et al 2002) TrkC Development of sensory neurons Liebl et al 1997) 1998; Hirota et al 2004), in which cytoplasmic domains of the receptor are no longer accessible to signaling proteins, rendering the receptor signaling incompetent. Moreover, the increasingly acidic lysosomal environment ( pH 4.0) promotes protein degradation.…”