Neurod1 regulates survival and formation of connections in mouse ear and brain.
The developing sensory neurons of the mammalian ear require two sequentially activated bHLH genes, Neurog1 and Neurod1, for their development. Neurons never develop in Neurog1 null mice, and most neurons die in Neurod1 null mutants, a gene upregulated by Neurog1. The surviving neurons of Neurod1 null mice are incompletely characterized in postnatal mice because of the early lethality of mutants and the possible compromising effect of the absence of insulin on peripheral neuropathies. Using Tg(Pax2-cre), we have generated a conditional deletion of floxed Neurod1 for the ear; this mouse is viable and allows us to investigate ear innervation defects of Neurod1 absence only in the ear. We have compared the defects in embryos and show an ear phenotype in conditional Neurod1 null mice comparable with the systemic Neurod1 null mouse. By studying postnatal animals, we show that Neurod1 not only is necessary for the survival of most spiral and many vestibular neurons, but is also essential for a segregated central projection of vestibular and cochlear afferents. In the absence of Neurod1 in the ear, vestibular and cochlear afferents enter the cochlear nucleus as a single mixed nerve. Neurites coming from vestibular and cochlear sensory epithelia project centrally to both cochlear and vestibular nuclei, in addition to their designated target projections. The peripheral innervation of the remaining sensory neurons is disorganized and shows collaterals of single neurons projecting to multiple endorgans, displaying no tonotopic organization of the organ of Corti or the cochlear nucleus. Pending elucidation of the molecular details for these Neurod1 functions, these data demonstrate that Neurod1 is not only a major factor for the survival of neurons but is crucial for the development of normal ear connections, both in the ear and in the central nervous system.
Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA.
Israt
I
Jahan
Jennifer
J
Kersigo
Ning
N
Pan
Bernd
B
Fritzsch
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000166:cytology* / Q000378:metabolism*; D002470:Cell Survival; D003051:Cochlea / Q000166:cytology / Q000294:innervation / Q000378:metabolism; D007758:Ear, Inner / Q000166:cytology* / Q000294:innervation* / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009415:Nerve Net / Q000378:metabolism*; D009475:Neurons, Afferent / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D014722:Vestibule, Labyrinth / Q000166:cytology / Q000294:innervation / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; C501008:Neurod1 protein, mouse