Opposing neuropeptides control cAMP signalling to regulate satiety
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TIR1-produced cAMP as a second messenger in transcriptional auxin signalling
The phytohormone auxin (Aux) is a principal endogenous developmental signal in plants. It mediates transcriptional reprogramming by a well-established canonical signalling mechanism. TIR1/AFB auxin receptors are F-box subunits of an ubiquitin ligase complex; after auxin perception, they associate with Aux/IAA transcriptional repressors and ubiquitinate them for degradation, thus enabling the activation of auxin response factor (ARF) transcription factors1,2,3. Here we revise this paradigm by showing that without TIR1 adenylate cyclase (AC) activity4, auxin-induced degradation of Aux/IAAs is not sufficient to mediate the transcriptional auxin response. Abolishing the TIR1 AC activity does not affect auxin-induced degradation of Aux/IAAs but renders TIR1 non-functional in mediating transcriptional reprogramming and auxin-regulated development, including shoot, root, root hair growth and lateral root formation. Transgenic plants show that local cAMP production in the vicinity of the Aux/IAA–ARF complex by unrelated AC enzymes bypasses the need for auxin perception and is sufficient to induce ARF-mediated transcription. These discoveries revise the canonical model of auxin signalling and establish TIR1/AFB-produced cAMP as a second messenger essential for transcriptional reprograming.
Consensus on the key characteristics of metabolism disruptors
Metabolism-disrupting agents (MDAs) are chemical, infectious or physical agents that increase the risk of metabolic disorders. Examples include pharmaceuticals, such as antidepressants, and environmental agents, such as bisphenol A. Various types of studies can provide evidence to identify MDAs, yet a systematic method is needed to integrate these data to help to identify such hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we developed 12 KCs of MDAs based on our knowledge of processes underlying metabolic diseases and the effects of their causal agents: (1) alters function of the endocrine pancreas; (2) impairs function of adipose tissue; (3) alters nervous system control of metabolic function; (4) promotes insulin resistance; (5) disrupts metabolic signalling pathways; (6) alters development and fate of metabolic cell types; (7) alters energy homeostasis; (8) causes inappropriate nutrient handling and partitioning; (9) promotes chronic inflammation and immune dysregulation in metabolic tissues; (10) disrupts gastrointestinal tract function; (11) induces cellular stress pathways; and (12) disrupts circadian rhythms. In this Consensus Statement, we present the logic that revealed the KCs of MDAs and highlight evidence that supports the identification of KCs. We use chemical, infectious and physical agents as examples to illustrate how the KCs can be used to organize and use mechanistic data to help to identify MDAs.
Sensory input, sex and function shape hypothalamic cell type development
Mammalian behaviour and physiology undergo major changes in early life. Young animals rely on conspecifics to meet their needs and start showing nutritional independence and sex-specific social interactions at weaning and puberty, respectively. How neuronal populations regulating homeostatic functions and social behaviours develop during these transitions remains unclear. We used paired transcriptomic and chromatin accessibility profiling to examine the developmental trajectories of neuronal populations in the hypothalamic preoptic region, where cell types with key roles in physiological and behavioural control have been identified1,2,3,4,5,6. These data show a marked diversity of developmental trajectories shaped by the sex of the animal, and the location and behavioural or physiological function of the corresponding cell types. We identify key stages of preoptic development, including early diversification, perinatal emergence of sex differences, postnatal maturation and refinement of signalling networks, and nonlinear transcriptional changes accelerating at the time of weaning and puberty. We assessed preoptic development in various sensory mutants and find a major role for vomeronasal sensing in the timing of preoptic cell type maturation. These results provide new insights into the development of neurons controlling homeostatic functions and social behaviours and lay ground for examining the dynamics of these functions in early life.
Proteolysis of TAM receptors in autoimmune diseases and cancer: what does it say to us?
Proteolytic processing of Receptor Tyrosine Kinases (RTKs) leads to the release of ectodomains in the extracellular space. These soluble ectodomains often retain the ligand binding activity and dampen canonical pathways by acting as decoy receptors. On the other hand, shedding the ectodomains may initiate new molecular events and diversification of signalling. Members of the TAM (TYRO3, AXL, MER) family of RTKs undergo proteolytic cleavage, and their soluble forms are present in the extracellular space and biological fluids. TAM receptors are expressed in professional phagocytes, mediating apoptotic cell clearance, and suppressing innate immunity. Enhanced shedding of TAM ectodomains is documented in autoimmune and some inflammatory conditions. Also, soluble TAM receptors are present at high levels in the biological fluids of cancer patients and are associated with poor survival. We outline the biology of TAM receptors and discuss how their proteolytic processing impacts autoimmunity and tumorigenesis. In autoimmune diseases, proteolysis of TAM receptors likely reflects reduced canonical signalling in professional phagocytes. In cancer, TAM receptors are expressed in the immune cells of the tumour microenvironment, where they control pathways facilitating immune evasion. In tumour cells, ectodomain shedding activates non-canonical TAM pathways, leading to epithelial-mesenchymal transition, metastasis, and drug resistance.
Inhibition of sympathetic tone via hypothalamic descending pathway propagates glucocorticoid-induced endothelial impairment and osteonecrosis of the femoral head
Osteonecrosis of the femoral head (ONFH) is a common complication of glucocorticoid (GC) therapy. Recent advances demonstrate that sympathetic nerves regulate bone homeostasis, and GCs lower the sympathetic tone. Here, we show that the dramatically decreased sympathetic tone is closely associated with the pathogenesis of GC-induced ONFH. GCs activate the glucocorticoid receptor (GR) but hinder the activation of the mineralocorticoid receptor (MR) on neurons in the hypothalamic paraventricular nucleus (PVN). This disrupts the balance of corticosteroid receptors (GR/MR) and subsequently reduces the sympathetic outflow in the PVN. Vascular endothelial cells rapidly react to inhibition of sympathetic tone by provoking endothelial apoptosis in adult male mice treated with methylprednisolone (MPS) daily for 3 days, and we find substantially reduced H-type vessels in the femoral heads of MPS-treated ONFH mice. Importantly, treatment with a GR inhibitor (RU486) in the PVN promotes the activation of MR and rebalances the ratio of GR and MR, thus effectively boosting sympathetic outflow, as shown by an increase in tyrosine hydroxylase expression in both the PVN and the sympathetic postganglionic neurons and an increase in norepinephrine levels in both the serum and bone marrow of the femoral head of MPS-treated mice. Rebalancing the corticosteroid receptors mitigates GC-induced endothelial impairment and ONFH and promotes angiogenesis coupled with osteogenesis in the femoral head, while these effects are abolished by chemical sympathectomy with 6-OHDA or adrenergic receptor-β2 (Adrb2) knockout. Furthermore, activating Adrb2 signaling in vivo is sufficient to rescue the GC-induced ONFH phenotype. Mechanistically, norepinephrine increases the expression of the key glycolytic gene 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) via Adrb2-cyclic AMP response element-binding protein (CREB) signaling. Endothelial-specific overexpression of PFKFB3 attenuates endothelial impairment and prevents severe osteonecrosis in MPS-treated Adrb2 knockout mice. Thus, GC inhibits sympathetic tone via the hypothalamic descending pathway, which, in turn, acts as a mediator of GC-induced ONFH.
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