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1.  Altered Phenotype of the Vestibular Organ in GLAST-1 Null Mice 
Various studies point to a crucial role of the high-affinity sodium-coupled glutamate aspartate transporter GLAST-1 for modulation of excitatory transmission as shown in the retina and the CNS. While 2–4-month-old GLAST-1 null mice did not show any functional vestibular abnormality, we observed profound circling behavior in older (7 months) animals lacking GLAST-1. An unchanged total number of otoferlin-positive vestibular hair cells (VHCs), similar ribbon numbers in VHCs, and an unchanged VGLUT3 expression in type II VHCs were detected in GLAST-1 null compared to wild-type mice. A partial loss of supporting cells and an apparent decline of a voltage-gated channel potassium subunit (KCNQ4) was observed in postsynaptic calyceal afferents contacting type I VHCs, together with a reduction of neurofilament- (NF200-) and vesicular glutamate transporter 1- (VGLUT1-) positive calyces in GLAST-1 null mice. Taken together, GLAST-1 deletion appeared to preferentially affect the maintenance of a normal postsynaptic/neuronal phenotype, evident only with increasing age.
PMCID: PMC3346889  PMID: 22350511
GLAST-1; vestibular hair cells; supporting cells; otoferlin; KCNQ4; VGLUT
2.  Stemness of the Organ of Corti Relates to the Epigenetic Status of Sox2 Enhancers 
PLoS ONE  2012;7(5):e36066.
In the adult mammalian auditory epithelium, the organ of Corti, loss of sensory hair cells results in permanent hearing loss. The underlying cause for the lack of regenerative response is the depletion of otic progenitors in the cell pool of the sensory epithelium. Here, we show that an increase in the sequence-specific methylation of the otic Sox2 enhancers NOP1 and NOP2 is correlated with a reduced self-renewal potential in vivo and in vitro; additionally, the degree of methylation of NOP1 and NOP2 is correlated with the dedifferentiation potential of postmitotic supporting cells into otic stem cells. Thus, the stemness the organ of Corti is related to the epigenetic status of the otic Sox2 enhancers. These observations validate the continued exploration of treatment strategies for dedifferentiating or reprogramming of differentiated supporting cells into progenitors to regenerate the damaged organ of Corti.
PMCID: PMC3343037  PMID: 22570694
3.  PARP1 Gene Knock-Out Increases Resistance to Retinal Degeneration without Affecting Retinal Function 
PLoS ONE  2010;5(11):e15495.
Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness in humans. Previously, excessive activation of enzymes belonging to the poly-ADP-ribose polymerase (PARP) group was shown to be involved in photoreceptor degeneration in the human homologous rd1 mouse model for RP. Since there are at least 16 different PARP isoforms, we investigated the exact relevance of the predominant isoform - PARP1 - for photoreceptor cell death using PARP1 knock-out (KO) mice. In vivo and ex vivo morphological analysis using optic coherence tomography (OCT) and conventional histology revealed no major alterations of retinal phenotype when compared to wild-type (wt). Likewise, retinal function as assessed by electroretinography (ERG) was normal in PARP1 KO animals. We then used retinal explant cultures derived from wt, rd1, and PARP1 KO animals to test their susceptibility to chemically induced photoreceptor degeneration. Since photoreceptor degeneration in the rd1 retina is triggered by a loss-of-function in phosphodiesterase-6 (PDE6), we used selective PDE6 inhibition to emulate the rd1 situation on non-rd1 genotypes. While wt retina subjected to PDE6 inhibition showed massive photoreceptor degeneration comparable to rd1 retina, in the PARP1 KO situation, cell death was robustly reduced. Together, these findings demonstrate that PARP1 activity is in principle dispensable for normal retinal function, but is of major importance for photoreceptor degeneration under pathological conditions. Moreover, our results suggest that PARP dependent cell death or PARthanatos may play a major role in retinal degeneration and highlight the possibility to use specific PARP inhibitors for the treatment of RP.
PMCID: PMC2990765  PMID: 21124852
4.  Deafness in TRβ-mutants is caused by malformation of the tectorial membrane 
Thyroid hormone receptor β (TRβ) dysfunction leads to deafness in humans and mice. Deafness in TRβ−/− mutant mice has been attributed to TRβ-mediated control of fast-activating BK current expression in inner hair cells (IHCs). However, normal hearing in young constitutive BKα−/− mutants contradicts this hypothesis. Here we show that mice with hair cell-specific deletion of TRβ after postnatal day (P) 11 have a delay in BKα expression but normal hearing, indicating that the origin of hearing loss in TRβ−/− mutant mice manifested before P11. Analyzing the phenotype of IHCs in constitutive TRβ−/− mice we found normal Ca2+ current amplitudes, exocytosis, and shape of compound action potential waveforms. In contrast, reduced DPOAEs and cochlear microphonics associated with an abnormal structure of the tectorial membrane and enhanced tectorin levels suggest that disturbed mechanical performance is the primary cause of deafness resulting from TRβ deficiency.
PMCID: PMC2748340  PMID: 19244534
hearing; TRβ; BK; conditional knockout mice; tectorin; exocytosis

Results 1-4 (4)