Shu-Ting Lin's scientific contributionswhile working at University of California, San Francisco (San Francisco, United States) and other institutions

Publications (12)

Publications citing this author (201)

    • Disease models Rodent models resemble Canavan disease (Matalon et al., 2000) and adult onset leukodystrophy (Heng et al., 2013) Twitcher does not accurately reflect Krabbe disease (Suzuki and Suzuki, 1983); Mutations in Abcd1 (Brites et al., 2009) do not recreate the cerebral demyelination observed in X-linked adrenoleukodystrophy (Schaumburg et al., 1975) of a substantially longer S phase in self-renewing division. Although the cell-cycle time during primate neurogenesis is significantly longer than in murine development, the primate brain undergoes a period of accelerated cell-cycle kinetics toward the end of embryonic neurogenesis (Kornack and Rakic, 1998 ).
    [Show abstract] [Hide abstract] ABSTRACT: Oligodendrocyte development has been studied for several decades, and has served as a model system for both neurodevelopmental and stem/progenitor cell biology. Until recently, the vast majority of studies have been conducted in lower species, especially those focused on rodent development and remyelination. In humans, the process of myelination requires the generation of vastly more myelinating glia, occurring over a period of years rather than weeks. Furthermore, as evidenced by the presence of chronic demyelination in a variety of human neurologic diseases, it appears likely that the mechanisms that regulate development and become dysfunctional in disease may be, in key ways, divergent across species. Improvements in isolation techniques, applied to primary human neural and oligodendrocyte progenitors from both fetal and adult brain, as well as advancements in the derivation of defined progenitors from human pluripotent stem cells, have begun to reveal the extent of both species-conserved signaling pathways and potential key differences at cellular and molecular levels. In this article, we will review the commonalities and differences in myelin development between rodents and man, describing the approaches used to study human oligodendrocyte differentiation and myelination, as well as heterogeneity within targetable progenitor pools, and discuss the advances made in determining which conserved pathways may be both modeled in rodents and translate into viable therapeutic strategies to promote myelin repair.
    Article · Mar 2016
    • The disruption of nuclear lamina proteins LMNB1, LBR, and MAN1 affects the period of CLO CK protein oscillations in both Drosophila cells and human U2OS cells, and MAN1 binds to Bmal1 promoter. This suggests that NE proteins play a role in the circadian control of transcription (Lin et al., 2014). The nucleus hosts various DNA repair mechanisms.
    [Show abstract] [Hide abstract] ABSTRACT: Circadian clocks are cell-autonomous timing mechanisms that organize cell functions in a 24-h periodicity. In mammals, the main circadian oscillator consists of transcription-translation feedback loops composed of transcriptional regulators, enzymes, and scaffolds that generate and sustain daily oscillations of their own transcript and protein levels. The clock components and their targets impart rhythmic functions to many gene products through transcriptional, posttranscriptional, translational, and posttranslational mechanisms. This, in turn, temporally coordinates many signaling pathways, metabolic activity, organelles' structure and functions, as well as the cell cycle and the tissue-specific functions of differentiated cells. When the functions of these circadian oscillators are disrupted by age, environment, or genetic mutation, the temporal coordination of cellular functions is lost, reducing organismal health and fitness.
    Full-text · Article · Oct 2016
    • The mechanism of action that underlies the phenotypic changes associated with increased miR- 23a expression were linked to repression of the Pten gene, a known regulator of myelination that acts to inhibit Akt-signaling and growth factor signaling such as IGF-1 (Harrington et al., 2010; De Paula et al., 2014). Additionally, a long non-coding RNA (2700046G09Rik) was also identified as a novel regulator of OL development and is a bona fide miR-23a regulated gene (Lin et al., 2013). Pathological studies of miRNA expression within the MS brain have compared miRNAs in both acute and chronic lesions, and the normal appearing white matter (NAWM; Junker et al., 2009).
    [Show abstract] [Hide abstract] ABSTRACT: Chronic demyelination is a hallmark of neurological disorders such as multiple sclerosis (MS) and several leukodystrophies. In the central nervous system (CNS), remyelination is a regenerative process that is often inadequate during these pathological states. In the MS context, in situ evidence suggests that remyelination is mediated by populations of oligodendrocyte progenitor cells (OPCs) that proliferate, migrate, and differentiate into mature, myelin-producing oligodendrocytes at sites of demyelinated lesions. The molecular programming of OPCs into mature oligodendrocytes is governed by a myriad of complex intracellular signaling pathways that modulate this process. Recent research has demonstrated the importance of specific and short non-coding RNAs, known as miRNAs (miRNAs), in regulating OPC differentiation and remyelination. Fortunately, it may be possible to take advantage of numerous developmental studies (both human and rodent) that have previously characterized miRNA expression profiles from the early neural progenitor cell to the late myelin-producing oligodendrocyte. Here we review much of the work to date and discuss the impact of miRNAs on OPC and oligodendrocyte biology. Additionally, we consider the potential for miRNA-mediated therapy in the context of remyelination and brain repair.
    Full-text · Article · Jun 2016
    • The PKC is involved in the phase shift of the firing rate of SCN cells in vitro (Schak and Harrington, 1999). The PLC/PKC system also mediates light (Bonsall and Lall, 2013; Lee et al., 2007) and food entrainment (Zhang et al., 2012), and it is involved in the effects of melatonin and NPY on phase advance in rodents (Biello et al., 1997; McArthur et al., 1997).
    [Show abstract] [Hide abstract] ABSTRACT: The liver is the most important link between the circadian system and metabolism. As a food entrainable oscillator, the hepatic clock needs to be entrained by food-related signals. The objective of the present study was to investigate the possible role of ghrelin (an orexigenic peptide mainly synthesized in the gastrointestinal tract) as an endogenous synchronizer of the liver oscillator in teleosts. To achieve this aim, we first examined the presence of ghrelin receptors in the liver of goldfish. Then, the ghrelin regulation of clock gene expression in the goldfish liver was studied. Finally, the possible involvement of the PLC/PKC and AC/PKA intracellular signaling pathways was investigated. Ghrelin receptor transcripts, ghs-r1a, are present in the majority of the goldfish hepatic cells. Ghrelin induces the mRNA expression of the positive (gbmal1a, gclock1a) and negative (gper genes) elements of the main loop of the molecular clock machinery, as well as of grev-erbα (auxiliary loop) in cultured liver. These effects are blocked, at least in part, by a ghrelin antagonist. Incubation of liver with a phospholipase-C inhibitor (U73122), a protein-kinase-C activator (phorbol-12-myristate-13-acetate) and a protein-kinase-C inhibitor (chelerythrine-chloride) demonstrates that the PLC-PKC pathway mediates such ghrelin actions. Studies with an adenylate cyclase activator (forskolin) and a protein-kinase-A inhibitor (H89) show that grev-erbα regulation could be due to an activation of protein-kinase-A. Taken together, present results show for the first time in vertebrates a direct action of ghrelin on hepatic clock genes and support a role for this hormone as a temporal messenger in the entrainment of liver circadian functions.
    Full-text · Article · Jan 2017
    • MAG is found to be enriched at peri-axonal regions of myelin sheaths in both the peripheral and central nervous system (Roda et al., 2016). Knockdown of Vlgr1 leads to reduced MAG expression, partly through absent posttranslational regulation as well as decreased slowing of proteasomal degradation (Shin et al., 2013). Signaling studies of VLGR1 reveals that downstream signaling occurs through Gα s /Gα q , activating PKA and protein kinase C (PKC)
    [Show abstract] [Hide abstract] ABSTRACT: Background: Adhesion G protein-coupled receptors (aGPCRs) are a large family of transmembrane proteins that play important roles in many processes during development, primarily through cell-cell and cell-extracellular matrix (ECM) interactions. In the nervous system, they have been linked to the complex process of myelination, both in the central and peripheral nervous system. Results: GPR126 is essential in Schwann cell-mediated myelination in the peripheral nervous system (PNS), while GPR56 is involved in oligodendrocyte development central nervous system (CNS) myelination. VLGR1 is another aGPCR that is associated with the expression of myelin-associated glycoprotein (MAG) which has inhibitory effects on the process of nerve repair. The ECM is composed of a vast array of structural proteins, three of which interact specifically with aGPCRs: collagen III/GPR56, collagen IV/GPR126, and laminin-211/GPR126. Conclusions: As druggable targets, aGPCRs are valuable in their ability to unlock treatment for a wide variety of currently debilitating myelin disorders. This article is protected by copyright. All rights reserved.
    Article · Nov 2016
    • Finally, lamins-the structural components of the filamentous protein meshwork essential to inner nuclear membrane structure-are also functionally engaged in maturation processes. Overexpression of lamin B1 leads to a disturbance of inner nuclear membrane proteins and of chromatin organization, mislocalization of NPCs, and impaired nuclear pore transport [201,202]. As a consequence, premature arrest of oligodendroglial differentiation, due to reduced myelin transcription and misguided myelin proteins, is observed [202].
    [Show abstract] [Hide abstract] ABSTRACT: A prominent feature of demyelinating diseases such as multiple sclerosis (MS) is the degeneration and loss of previously established functional myelin sheaths, which results in impaired signal propagation and axonal damage. However, at least in early disease stages, partial replacement of lost oligodendrocytes and thus remyelination occur as a result of resident oligodendroglial precursor cell (OPC) activation. These cells represent a widespread cell population within the adult central nervous system (CNS) that can differentiate into functional myelinating glial cells to restore axonal functions. Nevertheless, the spontaneous remyelination capacity in the adult CNS is inefficient because OPCs often fail to generate new oligodendrocytes due to the lack of stimulatory cues and the presence of inhibitory factors. Recent studies have provided evidence that regulated intracellular protein shuttling is functionally involved in oligodendroglial differentiation and remyelination activities. In this review we shed light on the role of the subcellular localization of differentiation-associated factors within oligodendroglial cells and show that regulation of intracellular localization of regulatory factors represents a crucial process to modulate oligodendroglial maturation and myelin repair in the CNS.
    Full-text · Article · Jul 2015
    • Lamin B1 is one of the major protein components of the nuclear lamina (Cortelli et al., 2012), and its duplication results in an increased expression of lamin B1 mRNA and protein in patient's brain tissue (Padiath and Fu, 2010). The molecular basis of ADLD is still unknown, but some mechanisms have been hypothesized to explain its occurrence (Lin et al., 2011; Ferrera et al., 2014; Giorgio et al., 2013; Bartoletti-Stella et al., 2015). Demyelination is characterized by preservation of axons and oligodendrocytes with decreased number of abnormal astrocytes (Padiath et al., 2006).
    [Show abstract] [Hide abstract] ABSTRACT: Background and purpose: Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare progressive neurological disorder caused by Lamin B1 duplication (LMNB1). Our aim was to investigate longitudinally the pattern of the autonomic dysfunction and the degree of neuropsychological involvement. Methods: Three related ADLD patients and one asymptomatic carrier of LMNB1 duplication underwent a standardized evaluation of autonomic nervous system, including cardiovascular reflexes, pharmacological testing, microneurography, skin biopsy, Metaiodobenzylguanidine scintigraphy and a complete neuropsychological battery. Results: An early neurogenic orthostatic hypotension was detected in all patients and confirmed by a low rise in noradrenaline levels on Tilt Test. However infusion of noradrenaline resulted in normal blood pressure rise as well as the infusion of clonidine. At the insulin tolerance test the increase in adrenaline resulted pathological in two out three patients. Microneurography failed to detect muscle sympathetic nerve activity bursts. Skin biopsy revealed a poor adrenergic innervation, while cardiac sympathetic nerves were normal. None of ADLD patients showed a global cognitive deficit but a selective impairment in the executive functions. Conclusion: Autonomic disorder in ADLD involves selectively the postganglionic sympathetic system including the sympatho-adrenal response. Cognitive involvement consisting in an early impairment of executive tasks that might precede brain MR abnormalities.
    Article · Feb 2016
    • At its most basic level, the cell-autonomous circadian clock is constituted by a transcriptional/translational negative feedback loop, in which activators (CLOCK/BMAL1) and repressors (PERIOD1–3[PER1–3]/CRYPTOCHROME1–2[CRY1–2]) are coordinately regulated (Hardin and Panda, 2013;Reppert and Weaver, 2002). We have shown that mutations in some of the core clock genes (PER2, PER3, Casein kinase Id, CRY2, DEC2) affect the timing of sleep-wake behavior or sleep duration in humans (He et al., 2009;Hirano et al., 2016b;Jones et al., 1999;Toh et al., 2001;Xu et al., 2005Xu et al., , 2007Zhang et al., 2016). Gene targeting or mutations of the clock genes in rodent models cause circadian phenotypes but also, in some cases, lead to metabolic dysfunction (Doi et al., 2010;Turek et al., 2005;Marcheva et al., 2010;Rudic et al., 2004;Shimba et al., 2011).
    [Show abstract] [Hide abstract] ABSTRACT: The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk), an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis). We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals.
    Full-text · Article · Apr 2017