Effects of Neurod1 Expression on Mouse and Human Schwannoma Cells

Abstract

Objectives The objective was to explore the effect of the proneuronal transcription factor neurogenic differentiation 1 (Neurod1, ND1) on Schwann cells (SC) and schwannoma cell proliferation. Methods Using a variety of transgenic mouse lines, we investigated how expression of Neurod1 effects medulloblastoma (MB) growth, schwannoma tumor progression, vestibular function, and SC cell proliferation. Primary human vestibular schwannoma (VS) cell cultures were transduced with adenoviral vectors expressing Neurod1. Cell proliferation was assessed by 5‐ethynyl‐2'‐deoxyuridine (EdU) uptake. Study Design Basic science investigation. Results Expression of Neurod1 reduced the growth of slow‐growing but not fast‐growing MB models. Gene transfer of Neurod1 in human schwannoma cultures significantly reduced cell proliferation in dose‐dependent way. Deletion of the neurofibromatosis type 2 (Nf2) tumor‐suppressor gene via Cre expression in SCs led to increased intraganglionic SC proliferation and mildly reduced vestibular sensory‐evoked potentials (VsEP) responses compared to age‐matched wild‐type littermates. The effect of Neurod1‐induced expression on intraganglionic SC proliferation in animals lacking Nf2 was mild and highly variable. Sciatic nerve axotomy significantly increased SC proliferation in wild‐type and Nf2‐null animals, and expression of Neurod1 reduced the proliferative capacity of both wild‐type and Nf2‐null SCs following nerve injury. Conclusion Expression of Neurod1 reduces slow‐growing MB progression and reduces human SC proliferation in primary VS cultures. In a genetic mouse model of schwannomas, we find some effects of Neurod1 expression; however, the high variability indicates that more tightly regulated Neurod1 expression levels that mimic our in vitro data are needed to fully validate Neurod1 effects on schwannoma progression. Level of Evidence NA Laryngoscope, 131:E259–E270, 2021

Head movement kinematics are altered during gaze stability exercises in vestibular schwannoma patients

“…We did not control for rehabilitation efforts in the present study, and therefore whether these results would differ if rehabilitation were explicitly controlled remains to be examined. Nonetheless our results are surprising given schwannomas tend to grow slowly 40 , theoretically allowing time for central compensation—in which case one might expect patients to perform normally pre-operatively 41 , 42 . Our data suggest pre-surgical rehabilitation may be beneficial, which is not currently considered as standard of care.…”

Neurog1, Neurod1, and Atoh1 are essential for spiral ganglia, cochlear nuclei, and cochlear hair cell development

“…Rhombomere-specific deletion of Atoh1 demonstrates that the cochlear nucleus forms from cells in rhombomeres 3–5 17 , 97 . Atoh1 expression is negatively regulated by Neurod1 in the cerebellum 41 , 98 , the cochlear hair cells and neurons 10 , and the intestine 99 but has not yet been shown for the cochlear nucleus. An additional bHLH gene, bHLHb5 97 , is also necessary to properly form the dorsal cochlear nucleus.…”

“…Not surprisingly, then, Atoh1/Neurod1 double null mice had little additional disorganized projection of cochlear afferents beyond that of Neurod1 alone 27 ( Figure 3 ). Atoh1/Neurod1 forms a complex interaction in the cerebellum 41 , 98 , 105 , which is useful for Neurod1 to convert astrocytes and Schwann cells into neurons 70 , 106 , 107 . Details are needed to determine whether deviations of central projections ( Figure 1 ) would occur in older stages after cochlear nuclei are formed 30 and dependence of cochlear nuclei on neuronal input declines 12 .…”

Development in the Mammalian Auditory System Depends on Transcription Factors

“…are found in the cochlear nucleus [38,138]. For example, Atoh1 is highly expressed in the ventral cochlear neurons, whereas Neurod1 is expressed more prominent in the dorsal cochlear nucleus (Figure 8; [18]).…”

“…Neurod1 and Atoh1 negatively interact in the cerebellum [38], in the cochlear HCs and neurons [28], and the intestine [45]. Also, differential levels and expression patterns of Atoh1 and Neurod1 are found in the cochlear nucleus [38,138]. For example, Atoh1 is highly expressed in the ventral cochlear neurons, whereas Neurod1 is expressed more prominent in the dorsal cochlear nucleus (Figure 8; [18]).…”