Neurotrophin-3 is a survival factor in vivo for early mouse trigeminal neurons - PubMed (original) (raw)

Neurotrophin-3 is a survival factor in vivo for early mouse trigeminal neurons

G A Wilkinson et al. J Neurosci. 1996.

Abstract

Mice lacking neurotrophin-3 (NT-3) have been shown previously to be born with severe sensory deficits. This study characterizes the developmental course of this deficit in the trigeminal sensory ganglion, which in NT-3 homozygous mutants contains only 35% of the normal number of neurons at birth. At embryonic day 10.5 (E10.5), normal numbers of neurons, as assessed by expression of neurofilament protein and of total cells, are present in the ganglia of mutant homozygotes. During the next 3 d (E10.5-E13.5), virtually all of the deficit develops, after which mutant animals retain only approximately 30% the normal number of neurons. Quantification of neuronal and neuronal precursor numbers in normal and mutant animals reveals that neurons are specifically depleted in the absence of NT-3. A deficiency in precursor proliferation is only seen after most of the neuronal deficit has developed. Numbers of apoptotic cells in the ganglia of mutant animals are elevated during this same interval, indicating that the neuronal deficit is caused, in large part, by increased cell death of embryonic neurons. To determine sources of NT-3 in the trigeminal system, we examined the expression pattern of beta-galactosidase in mice, in which lacZ has replaced the NT-3 coding exon. E10.5-E11.5 embryos exhibit intense reporter expression throughout the mesenchyme and epithelia of the first branchial arch. Beta-galactosidase expression in E13.5 embryos is largely confined to the oral epithelium and the mesenchyme underlying the skin. Throughout the E10.5-E13.5 interval, the trigeminal ganglion and its targets in the CNS do not express reporter activity. We conclude that NT-3 acts principally as a peripherally derived survival factor for early trigeminal neurons.

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Figures

Fig. 1.

Fig. 1.

Summary of the trigeminal phenotype in embryos lacking NT-3. For each pair of photographs, representative sections from wild-type (A, C, E) and mutant (B, D,F) animals are compared. These observations are quantitated in Tables 1 and 2. A, B, E13.5 material stained for NF-150 and counterstained for cresyl violet. Neurons are depleted relative to overall trigeminal populations.C, D, E13.5 material stained for cresyl violet. The density of pyknotic profiles is greatly elevated in mutants. Arrowheads indicate red blood cells.E, F, E11.5 material stained for BrdU incorporation by proliferating cells. Proliferation is unchanged at this stage. Scale bar, 100 μm.

Fig. 2.

Fig. 2.

Numbers of trigeminal neurons (squares) and precursor cells (diamonds) in wild-type (filled symbols) and NT-3 (open symbols) animals during development. Neurons in E10.5, E11.5, and E13.5 animals were counted as profiles immunopositive for NF-150 kDa protein. Precursors for those stages were calculated as total (Nissl) cells minus neurons. E15.5 and P0 neurons were identified on the basis of morphology in Nissl material. The mean ± SD of counts from three separate animals are shown for each point plotted.

Fig. 3.

Fig. 3.

Top. Changes in expression of a lacZ reporter construct inserted into the NT-3 locus. Whole mounts of heterozygous animals (see text). A, E9.5: staining is observed in the first branchial arch (arrow) and the anterior (a) and posterior (p) neuropores of the mesencephalon. B, E10.5 counterstained for TuJ1 to show axonal projections. The lacZ reaction was underdeveloped to allow visualization of axons. C, E11.5 embryo. Expression of NT-3 is strongest at the distal half of the maxillary process (Mx). D, E13.5 embryo. Reporter expression in the maxillary territory is strongest in the mystacial pad (MP) and distinctly less elsewhere.

Fig. 5.

Fig. 5.

Comparison of the peripheral branches of the trigeminal nerve in wild-type and mutant mice. A, Schematic drawing of an E13.5 embryo (adapted from Theiler, 1989) indicating the plane of section used for the camera lucida analysis. The thin ophthalmic branch (dorsal) and the thick maxillary branch (middle) were compared in wild-type, heterozygous, and mutant mice. The mandibular branch (ventral) travels obliquely to this plane and was not analyzed. ON, Optic nerve. B, Camera lucida drawing showing the ophthalmic and maxillary branches of the trigeminal nerve in a wild-type embryo. The ophthalmic nerve is_hatched_; the maxillary fascicles are_cross-hatched_. OX, Optic chiasm.C, Camera lucida drawing of the same complex in a mutant animal. The ophthalmic (hatched) and maxillary (cross-hatched) branches of the ganglion are both depleted (see Table 3). Scale bars, 100 μm.

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