Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis

Kopinke, Daniel; Roberson, Elle C.; Reiter, Jeremy F.

doi:10.1016/j.cell.2017.06.035

Cited by 180 publications

(307 citation statements)

References 58 publications

(84 reference statements)

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“…Consistent with the varied roles of cilia in neural development, an array of neurological deficits are among the most common hallmarks of ciliopathies (Lee and Gleeson, 2010;Youn and Han, 2018), highlighting the importance of these organelles in human health. In addition to their critical developmental functions, mounting evidence supports an important role for ciliary signaling in tissue regeneration and homeostasis in many adult organs, including the kidneys , skin (Croyle et al, 2011), skeletal muscle (Kopinke et al, 2017) and bone (Moore et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Bowie

Goetz

2019

Preprint

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Primary cilia are vital signaling organelles that extend from most types of cells, including neurons and glia. However, their function, particularly on neurons in the adult brain, remains largely unknown. Tau tubulin kinase 2 (TTBK2) is a critical regulator of ciliogenesis, and is also mutated a hereditary neurodegenerative disorder, spinocerebellar ataxia type 11 (SCA11).Here, we show that conditional knockout of Ttbk2 in adult mice results in degenerative cerebellar phenotypes that recapitulate aspects of human SCA11 including motor coordination deficits, loss of synaptic connections to Purkinje cells (PCs), and eventual loss of PCs. We also find that the Ttbk2 conditional mutant mice quickly lose cilia throughout the brain. We show that conditional knockout of the key ciliary trafficking gene Ift88 in adult mice results in nearly identical cerebellar phenotypes to those of the Ttbk2 knockout, supporting disruption of ciliary signaling as a key driver of these phenotypes. Our data suggest that primary cilia play an integral role in maintaining adult neuronal function, and offers novel insights into the mechanisms involved in neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Bowie

Goetz

2019

Preprint

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“…dWAT expansion largely stops when Shh is genetically deleted from the hair follicle epithelium, or when adipose precursors are made insensitive to Shh following the precursor-specific deletion of Smoothened 45 Moreover, skin-specific overexpression of Shh causes excessive dermal fat expansion to result in dWAT of nearly double the normal size 45 . Interestingly, the pro-adipogenic effect of Shh in dWAT contrasts with its inhibitory effect in other, non-skin adipose depots 69–72 .…”

Section: Cyclic Remodelling Of Dwatmentioning

confidence: 93%

Emerging nonmetabolic functions of skin fat

Guerrero‐Juarez

Plikus

2018

Nat Rev Endocrinol

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Although the major white adipose depots evolved primarily to store energy, secrete hormones and thermo-insulate the body, multiple secondary depots developed additional specialized and unconventional functions. Unlike any other fat tissue, dermal white adipose tissue (dWAT) evolved a large repertoire of novel features that are central to skin physiology, which we discuss in this Review. dWAT exists in close proximity to hair follicles, the principal appendages of the skin that periodically grow new hairs. Responding to multiple hair-derived signals, dWAT becomes closely connected to cycling hair follicles and periodically cycles itself. At the onset of new hair growth, hair follicles secrete activators of adipogenesis, while at the end of hair growth, a reduction in the secretion of activators or potentially, an increase in the secretion of inhibitors of adipogenesis, results in fat lipolysis. Hair-driven cycles of dWAT remodelling are uncoupled from size changes in other adipose depots that are controlled instead by systemic metabolic demands. Rich in growth factors, dWAT reciprocally signals to hair follicles, altering the activation state of their stem cells and modulating the pace of hair regrowth. dWAT cells also facilitate skin repair following injury and infection. In response to wounding, adipose progenitors secrete repair-inducing activators, while bacteria-sensing adipocytes produce antimicrobial peptides, thus aiding innate immune responses in the skin.

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“…Protein LSm14A is implicated in processing the assembly of processing bodies, involved in mRNA turnover, and can also bind to viral nucleic acids and initiate IFN-β production, contributing to innate immunity 28 . TIMP3 regulates the adipogenic differentiation of fibro/adipogenic progenitors (FAPs) in skeletal muscle, and its overrepresentation may explain the tendency for fat infiltration in aging muscle 29 . Consistent with this hypothesis, Perilipin 1 (PLIN1, β=0.014, p=0.0003), a lipid droplet-coating protein, and adipogenesis regulatory factor (ADIRF, β=0.01173, p=1.78E-05), a protein that is only expressed in adipose tissue, were among the most overrepresented proteins in old muscle.…”

Section: Focus On the Aging Biological Mechanismsmentioning

confidence: 99%

Aging Skeletal Muscle Proteomics Finds Changes in Spliceosome, Immune factors, Proteostasis and Mitochondria

Ubaida‐Mohien

Lyashkov

González-Freire

et al. 2019

Preprint

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A progressive decline of skeletal muscle strength with aging is a primary cause of mobility loss and frailty in older persons, but the molecular mechanisms of such decline are not fully understood. Here, using quantitative discovery proteomic data from skeletal muscle specimens collected from 58 healthy persons aged 20 to 87 years show that ribosomal proteins and proteins related to energetic metabolism, including those related to the TCA cycle, mitochondria respiration, and glycolysis were underrepresented in older persons.Proteins with important roles in innate and adaptive immunity, involved in proteostasis and regulation of alternative splicing were all overrepresented in muscle from older persons.Changes with aging of alternative splicing were confirmed by RNA-seq. Overall, older muscle has a profound deficit of energetic metabolism, a pro-inflammatory environment and increased proteostasis. Upregulation of the splicing machinery maybe an attempt to compensate for these changes and this could be tested in future studies. 20 30 40 50 60 70 80 −0.4 0.0 0.2 0.4 r 2 = 0.05, p = 0.13872 Figure 7Supplemental Information Aging Skeletal Muscle Proteomics Finds Changes in Spliceosome, Immune factors, Proteostasis and Mitochondria

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Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis

Cited by 180 publications

References 58 publications

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons

Emerging nonmetabolic functions of skin fat

Aging Skeletal Muscle Proteomics Finds Changes in Spliceosome, Immune factors, Proteostasis and Mitochondria

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