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Title: Combined In Silico and In Vivo Analyses Reveal Role of Hes1 in Taste Cell Differentiation}
Article:
Abstract:
The sense of taste is of critical importance to animal survival. Although studies of taste signal transduction mechanisms have provided detailed information regarding taste receptor calcium signaling molecules( TRCSMs, required for sweet/bitter/umami taste signal transduction), the ontogeny of taste cells is still largely unknown. We used a novel approach to investigate the molecular regulation of taste system development in mice by combining in silico and in vivo analyses. After discovering that TRCSMs colocalized within developing circumvallate papillae( CVP), we used computational analysis of the upstream regulatory regions of TRCSMs to investigate the possibility of a common regulatory network for TRCSM transcription. Based on this analysis, we identified Hes1 as a likely common regulatory factor, and examined its function in vivo. Expression profile analyses revealed that decreased expression of nuclear HES1 correlated with expression of type II taste cell markers. After stage E18, the CVP of Hes1−/− mutants displayed over 5-fold more TRCSM-immunoreactive cells than did the CVP of their wild-type littermates. Thus, according to our composite analyses, Hes1 is likely to play a role in orchestrating taste cell differentiation in developing taste buds.
Introduction:
Taste is one of the major chemosensory systems enabling animals to perceive crucial environmental stimuli. It performs the vital role of helping animals to identify favorable nutrition sources, as well as to avoid toxic substances, making taste a fundamental sensory recognition system that is required for survival[1],[2]. While the ontogeny of the other special sense organs has been studied in depth at a molecular level[3]–[5], the development of taste remains to be clarified. Taste buds are the sensory end organs for gustation, and are located on the epithelium of the tongue and palate. On the tongue, they reside on three types of papillae, i. e., fungiform, foliate, and circumvallate[2],[6],[7]. In adult mammals, each taste bud comprises groups of 50–100 spindle-shaped epithelial cells and a small number of proliferative cells[8],[9]. Taste bud cells are heterogeneous in terms of gene expression profiling of individual taste cells, as well as in their ultrastructural characteristics.[8],[10]–[14]. Ultrastructual studies have revealed three distinct anatomical types of spindle-shaped epithelial cells within each taste bud: type I( dark), type II( light), and type III( intermediate) cells[8],[10],[11]. Type II cells have a characteristic large round nucleus and are responsible for the sweet, bitter, and umami taste sensations[2],[6]–[8],[10]. These cells express a number of G protein–coupled receptors and common downstream transduction components called taste receptor calcium signaling molecules( TRCSMs; e. g., PLCβ2, gustducin[GNAT3], and IP3R3[ITPR3])[2],[6],[7],[10]. Although several studies have examined the lineage of taste cells[8],[10],[15],[16], the molecular mechanisms of cell differentiation in developing taste buds have remained elusive. We took a novel approach toward investigating taste cell development in mice by combining in silico and in vivo analyses of the TRCSM transcription regulatory network in type II taste cells.
Discussion:
Despite its importance, research regarding the molecular mechanisms of the development of the taste system has lagged behind that of the other special sense organs[3]–[5]. In our investigation of the molecular regulation of taste cell differentiation, we isolated key regulators of taste cell differentiation in early development by combining computational and experimental biology. Sharing gene expression regulatory components is an efficient way of regulating molecules within the same signal transduction pathway. TRCSMs are indeed expressed in the same population of cells, at least during the course of early taste system development. We performed in silico analysis of stretches of sequence up to 5 kb upstream of TCRSMs, some of which had been shown previously to drive TCRSM expression in taste cells in transgenic mice[25],[26]. Using computational analysis to determine which transcription factor binding sites were commonly found in the promoters of genes involved in the same regulatory network, we identified a number of putative transcription regulators. Similar procedures could be applied to analyses of other systems. It has been proposed that the development of taste buds is regulated by epithelial-mesenchymal interactions involving several different signaling pathways, such as Notch, Shh, Wnt, and BMP[23],[27]–[32]. Recent analyses of β-catenin and Sox2 suggest that they are involved in taste cell development, although the steps involved in differentiation have yet to be clarified[27]–[29]. The expression patterns of Notch signaling pathway–related genes indicate that the Notch signaling cascade may have a role during morphological differentiation of CVP[23]. Here, we report that the number of TRCSM-positive cells is more than 5-fold greater in Hes1−/− embryos than in their wild-type littermates at stages E18 and P0( Figure 5). Although we believe that the increase in TRCSM-positive cells observed in Hes1−/− mutants is due to premature expression of these marker proteins in the taste cell lineage, we cannot not exclude other possibilities, such as an increase in the total number of cells in CVP, or ectopic expression in cell types other than taste cells, in which expression of TRCSMs is normally repressed by HES1. Previous studies have proposed that a precursor population in the developing central nervous and hematopoietic systems expresses Hes1 to maintain its undifferentiated state, and that downregulation of Hes1 leads to differentiation[33]–[37]. Hes1 may have a similar function in the taste cell lineage, and a reduction in nuclear HES1 would thus trigger taste cell differentiation in CVP epithelium. In addition, we observed a reduction in nuclear HES1 in blood type H antigen– and SNAP25-positive cells( corresponding to type I and type III taste bud cells, respectively) in older animals( Figure 4). These observations support the possibility that Hes1 is indeed a common regulator of taste bud cell differentiation. Our computational analysis yielded several transcription factors that may be involved in the TRCSM regulatory network( Table S2). Our investigation of HES1, one of the candidate transcription factors, provides support for the utility of the computational approach. Our list of TRCSM regulators will be a valuable resource for future studies of taste development, leading to a better understanding of the process of taste cell differentiation. Further, it may be useful for designing therapies for taste disorders, such as loss of taste.
The sensation of taste is composed of five basic modalities: sweet , bitter , umami , sour , and salty . Specialized taste cells perceive the various chemical cues within food . About 100 taste cells assemble into onion-shaped clusters called taste buds , which are located on taste papillae in the tongue epithelium and on oral mucosa . Of the five taste modalities , the taste stimulants responsible for sweet , bitter , and umami tastes are recognized by a group of G protein–coupled taste receptors , and the signal transduction pathways utilized following receptor stimulation share common molecules . However , it is still largely unknown how these molecules are regulated during taste cell development . We performed computer analyses based on previously known information about signal transduction pathways involved in the taste-sensing system to identify taste stem cells/progenitor factors of type II taste cells ( responsible for sweet , bitter , and umami taste sensations ) . We found several transcription factors likely to bind to the regulatory regions of taste-related calcium signaling molecules ( TRCSMs ) , and identified Hes1 as a potential candidate for common regulatory factors of TRCSMs . In vivo analyses using wild-type and Hes1 mutant mice confirmed that Hes1 regulates differentiation of bitter- , sweet- , and umami-sensing cells .