Dlk1 Promotes a Fast Motor Neuron Biophysical Signature Required for Peak Force Execution

Müller, Daniel; Cherukuri, Pitchaiah; Henningfeld, Kristine A.; Poh, Chor Hoon; Wittler, Lars; Grote, Phillip; Schlüter, Oliver M.; Schmidt, Jennifer V.; Laborda, Jorge; Bauer, Steven R.; Brownstone, Robert M.; Marquardt, Till

doi:10.1126/science.1246448

Cited by 65 publications

(97 citation statements)

References 42 publications

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“…A growing body of evidence supports the function of DLK1 as a noncanonical NOTCH receptor ligand that regulates Notch signaling (41)(42)(43). In this regard, it is worth mentioning that Notch signaling has been shown to be involved in insulin sensitivity.…”

Section: Discussionmentioning

confidence: 97%

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic b-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic b-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1 2/2 ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1 2/2 mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic b-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.A growing body of work indicates that bone is an endocrine organ that regulates glucose metabolism through, in part, the hormone osteocalcin (OCN). OCN signals in b-cells through its bona fide receptor Gprotein-coupled receptor (Gprc6a) to increase b-cell proliferation and insulin secretion and acts on peripheral tissues to increase energy expenditure (1-3). In turn, insulin signaling in osteoblasts (OBs) stimulates the activation of OCN by promoting its decarboxylation (Glu-OCN) through the bone resorption arm of bone remodeling (1,4). The physiological relevance of these findings have been supported through studies demonstrating skeleton as a site of insulin resistance in mice fed a high-fat diet (5). Moreover, patients with a dominant negative mutation in Gprc6a show evidence of glucose intolerance (3). In all likelihood, the Glu-OCN-insulin feed-forward loop must be under a negative regulation to protect from hypoglycemia. Soluble factors responsible for this regulation have not yet been identified despite the demonstrated ability of transcription factors activating transcription factor 4 (ATF4) and forkhead box protein O1 (FoxO1) to regulate glucose metabolism through a negative regulation of OCN bioavailability (6,7). Delta like-1 (DLK1), also known as preadipocyte factor-1 (Pref-1), is a transmembrane protein belonging to the Notch/serrate/delta family (8,9). The full ectodomain of DLK1 is proteolytically cleaved to generate a soluble active protein named fetal antigen-1 (FA1), which is secreted by endocrine cells of pancreas, ovary, Leydig cells of the testis, adrenal glands, and pituitary gland (10). DLK1 has

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Section: Discussionmentioning

confidence: 97%

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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“…It is also called Pref-1, a factor involved in adipogenesis (20,21,50). Some previous studies had implicated DLK1 and its homologs as positive regulators in LIN-12/ NOTCH signaling (25,51,52), whereas other studies had shown the opposite or no effect of DLK1 on NOTCH signaling (26,27,50,(53)(54)(55)(56). These seemingly contradictory results could be due to different experimental systems used in different studies.…”

Section: Discussionmentioning

confidence: 99%

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

Shamis

Cullen²,

Liu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Zfp57 is a maternal–zygotic effect gene that maintains genomic imprinting. Here we report that Zfp57 mutants exhibited a variety of cardiac defects including atrial septal defect (ASD), ventricular septal defect (VSD), thin myocardium, and reduced trabeculation. Zfp57 maternal-zygotic mutant embryos displayed more severe phenotypes with higher penetrance than the zygotic ones. Cardiac progenitor cells exhibited proliferation and differentiation defects in Zfp57 mutants. ZFP57 is a master regulator of genomic imprinting, so the DNA methylation imprint was lost in embryonic heart without ZFP57. Interestingly, the presence of imprinted DLK1, a target of ZFP57, correlated with NOTCH1 activation in cardiac cells. These results suggest that ZFP57 may modulate NOTCH signaling during cardiac development. Indeed, loss of ZFP57 caused loss of NOTCH1 activation in embryonic heart with more severe loss observed in the maternal-zygotic mutant. Maternal and zygotic functions of Zfp57 appear to play redundant roles in NOTCH1 activation and cardiomyocyte differentiation. This serves as an example of a maternal effect that can influence mammalian organ development. It also links genomic imprinting to NOTCH signaling and particular developmental functions.

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“…Among alpha-MNs, fast-fatigable MNs are particularly vulnerable to ALS. They exhibit highest thresholds for excitation, are recruited infrequently to produce brief and intense force, fire in bursts, and might express higher levels of calcium-activated SK channels (Saxena and Caroni, 2011;Mü ller et al, 2014). In contrast, least vulnerable slow MNs exhibit low recruitment thresholds, are recruited frequently during wakefulness, and exhibit tonic firing.…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 91%

From Intrinsic Firing Properties to Selective Neuronal Vulnerability in Neurodegenerative Diseases

Roselli

Caroni

2015

Neuron

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Neurodegenerative diseases (NDDs) involve years of gradual preclinical progression. It is widely anticipated that in order to be effective, treatments should target early stages of disease, but we lack conceptual frameworks to identify and treat early manifestations relevant to disease progression. Here we discuss evidence that a focus on physiological features of neuronal subpopulations most vulnerable to NDDs, and how those features are affected in disease, points to signaling pathways controlling excitation in selectively vulnerable neurons, and to mechanisms regulating calcium and energy homeostasis. These hypotheses could be tested in neuronal stress tests involving animal models or patient-derived iPS cells.

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Dlk1 Promotes a Fast Motor Neuron Biophysical Signature Required for Peak Force Execution

Cited by 65 publications

References 42 publications

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

Maternal and zygotic Zfp57 modulate NOTCH signaling in cardiac development

From Intrinsic Firing Properties to Selective Neuronal Vulnerability in Neurodegenerative Diseases

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