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 186 publications

(329 citation statements)

References 58 publications

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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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“…However, it is known that different modes of injury have unique characteristics. For example, glycerol injury results in a more adipogenic phenotype compared to other modes of injury (22). Although we and others have begun to characterize the skeletal muscle response to ischemia (9,10,12,23), the role of MPCs in this process remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

Muscle progenitor cells are required for the regenerative response and prevention of adipogenesis after limb ischemia

Abbas

Olivere

Padgett

et al. 2020

Preprint

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Peripheral artery disease (PAD) is nearly as common as coronary artery disease, but few effective treatments exist, and it is associated with significant morbidity and mortality. Although PAD studies have focused on the vascular response to ischemia, skeletal muscle cells play a critically important role in determining the phenotypic manifestation of PAD. Here, we demonstrate that genetic ablation of Pax7 + muscle progenitor cells (MPCs, or satellite cells) in a murine model of hind limb ischemia (HLI) resulted in a complete absence of normal muscle regeneration following ischemic injury, despite a lack of morphological or physiological changes in resting muscle. Compared to ischemic muscle of control mice (Pax7 WT ), the ischemic limb of Pax7-deficient mice (Pax7 ∆ ) was unable to generate significant force 7-or 28-days after HLI in ex vivo force measurement studies. A dramatic increase in adipose infiltration was observed 28 days after HLI in Pax7 ∆ mice, which replaced functional muscle. To investigate the mechanism of this adipogenic change, mice with inhibition of fibro/adipogenic precursors (FAPs), another pool of MPCs, were subjected to HLI. Inhibition of FAPs decreased muscle adipose fat but increased fibrosis. MPCs cultured from mouse muscle tissue failed to form myotubes in vitro following depletion of satellite cells in vivo, and they displayed an increased propensity to differentiate into fat in adipogenic medium. Importantly, this phenotype was recapitulated in patients with critical limb ischemia (CLI), the most severe form of PAD. Skeletal muscle samples from CLI patients demonstrated an increase in adipose deposition in more ischemic regions of muscle, which corresponded with a decrease in the number of satellite cells in those regions.Collectively, these data demonstrate that Pax7 + MPCs are required for normal muscle regeneration after ischemic injury, and they suggest that targeting muscle regeneration may be an important therapeutic approach to prevent muscle degeneration in PAD.

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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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Ciliary Hedgehog Signaling Restricts Injury-Induced Adipogenesis

Cited by 186 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

Muscle progenitor cells are required for the regenerative response and prevention of adipogenesis after limb ischemia

Emerging nonmetabolic functions of skin fat

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