SOX2 is essential for maintaining neurosensory stem cell properties, although its involvement in the early neurosensory development of cranial placodes remains unclear. To address this, we used Foxg1-Cre to conditionally delete Sox2 during eye, ear, and olfactory placode development. Foxg1-Cre mediated early deletion of Sox2 eradicates all olfactory placode development, and disrupts retinal development and invagination of the lens placode. In contrast to the lens and olfactory placodes, the ear placode invaginates and delaminates NEUROD1 positive neurons. Furthermore, we show that SOX2 is not necessary for early ear neurogenesis, since the early inner ear ganglion is formed with near normal central projections to the hindbrain and peripheral projections to the undifferentiated sensory epithelia of E11.5-12.5 ears. However, later stages of ear neurosensory development, in particular, the late forming auditory system, critically depend on the presence of SOX2. Our data establish distinct differences for SOX2 requirements among placodal sensory organs with similarities between olfactory and lens but not ear placode development, consistent with the unique neurosensory development and molecular properties of the ear.
- MeSH
- apoptóza MeSH
- myši knockoutované MeSH
- myši MeSH
- neurogeneze * MeSH
- nosní sliznice embryologie metabolismus MeSH
- oční čočka embryologie metabolismus MeSH
- transkripční faktory SOXB1 genetika metabolismus MeSH
- vnitřní ucho cytologie embryologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Ear development requires the transcription factors ATOH1 for hair cell differentiation and NEUROD1 for sensory neuron development. In addition, NEUROD1 negatively regulates Atoh1 gene expression. As we previously showed that deletion of the Neurod1 gene in the cochlea results in axon guidance defects and excessive peripheral innervation of the sensory epithelium, we hypothesized that some of the innervation defects may be a result of abnormalities in NEUROD1 and ATOH1 interactions. To characterize the interdependency of ATOH1 and NEUROD1 in inner ear development, we generated a new Atoh1/Neurod1 double null conditional deletion mutant. Through careful comparison of the effects of single Atoh1 or Neurod1 gene deletion with combined double Atoh1 and Neurod1 deletion, we demonstrate that NEUROD1-ATOH1 interactions are not important for the Neurod1 null innervation phenotype. We report that neurons lacking Neurod1 can innervate the flat epithelium without any sensory hair cells or supporting cells left after Atoh1 deletion, indicating that neurons with Neurod1 deletion do not require the presence of hair cells for axon growth. Moreover, transcriptome analysis identified genes encoding axon guidance and neurite growth molecules that are dysregulated in the Neurod1 deletion mutant. Taken together, we demonstrate that much of the projections of NEUROD1-deprived inner ear sensory neurons are regulated cell-autonomously.
- MeSH
- apoptóza genetika MeSH
- axony metabolismus MeSH
- biologické modely MeSH
- buněčná diferenciace genetika MeSH
- Cortiho orgán patologie MeSH
- delece genu MeSH
- epitel metabolismus MeSH
- ganglion spirale metabolismus MeSH
- mutace genetika MeSH
- myši knockoutované MeSH
- nervová vlákna metabolismus MeSH
- proteiny nervové tkáně genetika metabolismus MeSH
- regulace genové exprese MeSH
- stanovení celkové genové exprese MeSH
- transkripční faktory bHLH genetika metabolismus MeSH
- transkripční faktory SOXB1 metabolismus MeSH
- vláskové buňky metabolismus patologie ultrastruktura MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Hearing depends on extracting frequency, intensity, and temporal properties from sound to generate an auditory map for acoustical signal processing. How physiology intersects with molecular specification to fine tune the developing properties of the auditory system that enable these aspects remains unclear. We made a novel conditional deletion model that eliminates the transcription factor NEUROD1 exclusively in the ear. These mice (both sexes) develop a truncated frequency range with no neuroanatomically recognizable mapping of spiral ganglion neurons onto distinct locations in the cochlea nor a cochleotopic map presenting topographically discrete projections to the cochlear nuclei. The disorganized primary cochleotopic map alters tuning properties of the inferior colliculus units, which display abnormal frequency, intensity, and temporal sound coding. At the behavioral level, animals show alterations in the acoustic startle response, consistent with altered neuroanatomical and physiological properties. We demonstrate that absence of the primary afferent topology during embryonic development leads to dysfunctional tonotopy of the auditory system. Such effects have never been investigated in other sensory systems because of the lack of comparable single gene mutation models.SIGNIFICANCE STATEMENT All sensory systems form a topographical map of neuronal projections from peripheral sensory organs to the brain. Neuronal projections in the auditory pathway are cochleotopically organized, providing a tonotopic map of sound frequencies. Primary sensory maps typically arise by molecular cues, requiring physiological refinements. Past work has demonstrated physiologic plasticity in many senses without ever molecularly undoing the specific mapping of an entire primary sensory projection. We genetically manipulated primary auditory neurons to generate a scrambled cochleotopic projection. Eliminating tonotopic representation to auditory nuclei demonstrates the inability of physiological processes to restore a tonotopic presentation of sound in the midbrain. Our data provide the first insights into the limits of physiology-mediated brainstem plasticity during the development of the auditory system.
- MeSH
- chování zvířat fyziologie MeSH
- colliculus inferior anatomie a histologie fyziologie MeSH
- ganglion spirale cytologie fyziologie MeSH
- mapování mozku MeSH
- mezencefalon embryologie fyziologie MeSH
- myši knockoutované MeSH
- myši MeSH
- nucleus cochlearis anatomie a histologie fyziologie MeSH
- sluch fyziologie MeSH
- sluchová percepce genetika fyziologie MeSH
- těhotenství MeSH
- transkripční faktory bHLH genetika fyziologie MeSH
- úleková reakce genetika fyziologie MeSH
- vestibulární aparát anatomie a histologie fyziologie MeSH
- vnímání výšky zvuku fyziologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
The role of Sox2 in neurosensory development is not yet fully understood. Using mice with conditional Islet1-cre mediated deletion of Sox2, we explored the function of Sox2 in neurosensory development in a model with limited cell type diversification, the inner ear. In Sox2 conditional mutants, neurons initially appear to form normally, whereas late- differentiating neurons of the cochlear apex never form. Variable numbers of hair cells differentiate in the utricle, saccule, and cochlear base but sensory epithelium formation is completely absent in the apex and all three cristae of the semicircular canal ampullae. Hair cells differentiate only in sensory epithelia known or proposed to have a lineage relationship of neurons and hair cells. All initially formed neurons lacking hair cell targets die by apoptosis days after they project toward non-existing epithelia. Therefore, late neuronal development depends directly on Sox2 for differentiation and on the survival of hair cells, possibly derived from common neurosensory precursors.
- MeSH
- delece genu MeSH
- myši transgenní MeSH
- myši MeSH
- neurogeneze fyziologie MeSH
- sakulus a utrikulus cytologie embryologie MeSH
- transkripční faktory SOXB1 genetika metabolismus MeSH
- vláskové buňky cytologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
INTRODUCTION: The aim of the study was to evaluate and compare the efficacy of standard unfractionated heparin (UFH) and low-molecular weight heparins (LMWH's). MATERIALS AND METHODS: We modified a previously published rabbit model of arterial thrombosis prevention [1,2] to compare unfractionated heparin and two different doses of two low-molecular weight heparin fragments--nadroparin and enoxaparin. Thrombosis in the distal aorta was triggered by vessel wall injury and critical stenosis. Blood flow in the damaged arterial segment was monitored by a flow probe placed distal to the constrictor. The primary endpoints of the study were: (1) cumulative flow, (2) time to occlusion and (3) residual clot weight. Thirty six animals were split into 6 groups with six animals in each group. Control groups were given saline or heparin and four more groups were used to compare LMWH's at 2 different doses. RESULTS: In our study, all treatments were superior to the saline control group (alpha
- MeSH
- arterie MeSH
- enoxaparin terapeutické užití MeSH
- heparin nízkomolekulární terapeutické užití MeSH
- heparin terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- králíci MeSH
- nadroparin terapeutické užití MeSH
- trombóza farmakoterapie prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
