Aging-related upregulation of the homeobox gene caudal represses intestinal stem cell differentiation in Drosophila

Abstract

The differentiation efficiency of adult stem cells undergoes a significant decline in aged animals, which is closely related to the decline in organ function and age-associated diseases. However, the underlying mechanisms that ultimately lead to this observed decline of the differentiation efficiency of stem cells remain largely unclear. This study investigated Drosophila midguts and identified an obvious upregulation of caudal (cad), which encodes a homeobox transcription factor. This factor is traditionally known as a central regulator of embryonic anterior-posterior body axis patterning. This study reports that depletion of cad in intestinal stem/progenitor cells promotes quiescent intestinal stem cells (ISCs) to become activate and produce enterocytes in the midgut under normal gut homeostasis conditions. However, overexpression of cad results in the failure of ISC differentiation and intestinal epithelial regeneration after injury. Moreover, this study suggests that cad prevents intestinal stem/progenitor cell differentiation by modulating the Janus kinase/signal transducers and activators of the transcription pathway and Sox21a-GATAe signaling cascade. Importantly, the reduction of cad expression in intestinal stem/progenitor cells restrained age-associated gut hyperplasia in Drosophila. This study identified a function of the homeobox gene cad in the modulation of adult stem cell differentiation and suggested a potential gene target for the treatment of age-related diseases induced by age-related stem cell dysfunction.

Stress Induced Activation of LTR Retrotransposons in the Drosophila melanogaster Genome

“…The role of these TFs is in the development of the organism, regulation of differentiation processes, and maintenance of stem cells. For example, HSF is necessary for early larval development and oogenesis, as well as the development of Drosophila [39]; cad is important for the determination of the anterior-posterior axis of the embryo, as well as maintaining stem cells in the gut [40]; slbo and Trlare are involved in cell migration during oogenesis [41]; and Lag-1 regulates differentiation of stem cells [42]. Thus, TE activation under stress does not occur directly in response to stress but under the influence of tissue regeneration processes that are triggered by this stress.…”

HMBOX1, a member of the homeobox family: current research progress

“…The homeobox gene has been shown to be involved in regulating the differentiation of various tissues and cells [7][8][9][10][11], including HOXC8 suppression in osteo-/ dentinogenic differentiation [7], NKX2-3 and NKX2-4 in acute myeloid leukemia subtype formation [8], and Six3 in medium spiny neuron differentiation [10] and caudal repression of intestinal stem cell differentiation [11]. As a member of the homeobox family, HMBOX1 also plays an important role in cell differentiation and functional maintenance.…”

De novo apical domain formation inside the Drosophila adult midgut epithelium

“…Quiescent enteroblasts are morphologically indistinguishable from ISCs until they are activated to differentiate in response to damage or nutrient-dependent signals (Nászai et al, 2015; O’Brien et al, 2011; Rojas Villa et al, 2019). Over the past 15 years multiple signaling pathways have been found to control ISC proliferation and differentiation, but much less is known about how differentiating enteroblasts insert into the midgut epithelium and polarize to form an apical domain(Antonello et al, 2015; Chen et al, 2016; He et al, 2018; Jiang and Edgar, 2011; Sasaki and Nishimura, 2021; Wang and Hou, 2010; Wu et al, 2021).…”