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Anatomy of the Respiratory Neural Network
Published in Susmita Chowdhuri, M Safwan Badr, James A Rowley, Control of Breathing during Sleep, 2022
Christopher A Del Negro, Christopher G Wilson
Parabrachial and Kölliker-Fuse neurons are derived from Atoh-1 expressing progenitors. Their relationship to Atoh-1 expression is noteworthy because this transcription factor is critical for the development of other important respiratory nuclei like the pFV (and perhaps pFL). And it is consistent with a general role for Atoh-1 in patterning key respiratory sites and nuclei (143, 168).
The Paneth Cell and Its Role in the Development of NEC
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Brian A. Juber, Steven J. McElroy
Several biochemical pathways have been implicated in the biology of Paneth cell development (Figure 45.2). The Wnt/β-catenin pathway is an important stimulator of Paneth cell development, and activation of this signaling pathway induces Paneth cell differentiation in both the small intestine and colon (16, 17). However, the Wnt signal pathway and its relationship to Paneth cell development is complex and still not completely elucidated. Genetic knockout of LGR-5, a downstream target of Wnt signaling, has been shown to produce precocious Paneth cell differentiation in fetal intestine (17, 18). This contradictory data may be due to alterations in negative-feedback mediators on the Wnt pathway. Another important pathway in Paneth cell development and differentiation is through activation of protein kinase C λ/ι, which results in activation of the transcription factors Atoh1 and Gfi1 (19). Loss of Atoh1 in transgenic mice results in ablation of Paneth cell lineages (19, 20). In addition, genetic loss of the neuregulin receptor ErbB3 in mice results in unchecked activity of the transcription factor Atoh1 and induces precocious Paneth cell development (21). However, it is important to note that modifications to Atoh1 signal pathways also affect goblet cell differentiation (20), so understanding of Paneth cell differentiation is still incomplete.
Future Therapies
Published in James R. Tysome, Rahul G. Kanegaonkar, Hearing, 2015
An alternative strategy for auditory hair cell degeneration is to use regeneration. Several strategies have been reported. The first is to induce proliferation of mature hair cells by deleting genes that normally regulate the cell cycle. However, this approach has shown limited success in animals models, and there are concerns that such proliferation could proceed uncontrolled. Another approach is the conversion of cochlear supporting cells into hair cells, in particular exploiting overexpression of the gene Atoh1, a known regulator of hair cell differentiation that has shown promise in animal trials and is now entering human trials. The final approach is to use stem cells, either undifferentiated embryonic stem cells or stem cells from within the cochlea. Stem cells have been successfully induced to differentiate into primitive cochlear hair cells, but these cells show little evidence of integration with auditory neurons, meaning they are likely to be non-functional. There is much potential for hair cell regeneration as a new treatment, particularly for presbyacusis, but achieving clinically important results may still be a distant goal.
Experimental drugs for the prevention or treatment of sensorineural hearing loss
Published in Expert Opinion on Investigational Drugs, 2023
Judith S Kempfle, David H. Jung
Researchers have therefore sought to understand the underlying molecular mechanisms that enable hair cell regeneration in birds, amphibians, and fish, in the hopes that their findings might one day be extrapolated to the mammalian and human inner ear. The discovery of the transcription factor Atoh1 (Math1) was the first major milestone toward inner ear regeneration in mammals [82–85]. Atoh1 activation proved to be necessary and sufficient to drive inner ear progenitors or nonsensory cells within the organ of Corti toward a hair cell lineage and initiate the inner ear hair cell phenotype [86,87]. The upstream governing pathways and transcription factors leading to Atoh1 activation provided ample new targets for drug development [88,89]. Specifically, the interplay between the Notch and Wnt pathways for upstream stimulation of Atoh1 has taken center stage in the field of hair cell regeneration [90–94].
Direct cellular reprogramming and inner ear regeneration
Published in Expert Opinion on Biological Therapy, 2019
Patrick J. Atkinson, Grace S. Kim, Alan G. Cheng
Independent studies have shown that the effectiveness of Atoh1 overexpression is rather limited in the adult cochlea, where little to no functional recovery was observed [58,59,62,63,68]. Similarly, Atoh1 overexpression induces ectopic hair cells in the neonatal utricle with varied results reported in the mature organ [69,70]. Despite these mixed results in preclinical studies, they led to the opening of a clinical trial assessing the safety and potential benefits of Atoh1 transfection in hearing loss patients (NCT02132130). The results may shed lights firstly on the safety of inner ear viral delivery, and possibly also on the efficacy of a single-factor reprogramming approach, which has been found effective in some organ systems [71–73]. In a recent study in the visual system of mature mice, for example, forced expression of the transcription factor Ascl1 in combination with a histone deacetylase inhibitor, was able to stimulate functional retinal neurons from Müller glia [74]. Without the addition of the histone deacetylase inhibitor, however, no regeneration was observed. This suggests that epigenetic regulators can play an important role in governing cellular reprogramming, a topic which will be discussed in the following section.
Celastrol enhances Atoh1 expression in inner ear stem cells and promotes their differentiation into functional auditory neuronal-like cells
Published in Organogenesis, 2018
Zhao Han, Yu-yan Gu, Ning Cong, Rui Ma, Fang-lu Chi
Atoh1 (Atonal BHLH Transcription Factor 1) is the member of the basic helix-loop-helix (BHLH) transcription factor family. Through collaboration with TCF3/E47, Atoh1 activates E box-dependent transcription and plays critical roles in differentiation of several subsets of neural cells.8 It was reported that the transcription activity of Atoh1 was readily antagonized by the negative regulator of neurogenesis HES1.9 Loss-of-function of Atoh1 has been identified in the Goblet cell carcinoid and infratentorial cancer.10 More importantly, Atoh1 is the first gene characterized to be involved in inner ear development, and especially plays a fundamental role in hair cell differentiation.11 During inner ear formation, the Atoh1-positive cells are committed to generate sensory hair cells and indispensable for their development, survival, differentiation and maturation. The ectopic introduction of Atoh1 led to formation of supernumerary cochlear sensory hair cells,12 and aberrant overexpression of Atoh1 stimulated trans-differentiation of supporting cells to hair cells.13 Although investigations into the underlying mechanism have identified Pou4f3, Gfi1 and Myosin 7a as potent downstream effectors,14 the comprehensive understanding of Atoh1 in the biology of auditory system is still to be fulfilled.