Molecular and Cellular Neuroscience Commons^™

The Rpm-1/Phr Signaling Hub Modulates Tau-Induced Neurodegeneration Through Regulation Of Microtubule Stability And Mapk Pathways In C. Elegans, Xinxing Ding

Theses and Dissertations

Neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, are characterized by the accumulation of pathological tau proteins and progressive neuronal loss. Although research regarding tau-mediated toxicity is extensive, the specific pathology that determine whether neurons maintain homeostasis or succumb to collapse under tau-induced stress remain incompletely elucidated. A central, yet still insufficiently understood, feature of these diseases is the disruption of the microtubule (MT) cytoskeleton . The PHR protein family is evolutionarily highly conserved; within this family, RPM-1 in C. elegans functions as an intracellular signaling hub that regulates axon development, synapse formation, axon termination, and various microtubule-associated processes. This …

Rhythms Of Hippocampal Function And Memory After Moderate Prenatal Alcohol Exposure, Lilliana May Sanchez

Psychology ETDs

Fetal Alcohol Spectrum Disorders involve morphologic and neurobiological abnormalities in offspring subjected to prenatal alcohol exposure. Although not as well studied as high exposure, moderate prenatal alcohol exposure represents the most common and undetected form in humans. While learning and memory deficits have been well characterized at the behavioral level in humans with Fetal Alcohol Spectrum Disorders and in animal models of moderate prenatal alcohol exposure, few studies have determined the circuit or systems level mechanisms of the behavioral deficits. A complete understanding of the neural bases of memory deficits after moderate prenatal alcohol exposure is needed to ultimately identify …

Exploring Anticholinergic Neurotoxicity: Diphenhydramine's Impact On Neuro-2a Cell Morphology, Expression, And Viability, Jordan B. Mcintyre

Honors Undergraduate Theses

Anticholinergic medications, such as diphenhydramine (commonly known as Benadryl), are increasingly recognized for their association with cognitive impairment and neurodegenerative disease. These medications, which inhibit the action of acetylcholine, a neurotransmitter essential for the formation and utilization of the central and peripheral nervous system, have been implicated in conditions such as dementia and may impact fundamental cellular processes like neurogenesis and cell proliferation. This study investigates the effects of diphenhydramine on neurogenesis when introduced to Neuro-2a cells during differentiation. For all studies cells were plated on coverslips or in 6-well plates with differentiation media containing 0 ng/mL, 50 ng/mL, …

The Role Of Androgen Receptor And B2/Alu Sine Rna Interaction In Hippocampal Dendritic Development, Troy A. Richter

Graduate Doctoral Dissertations

Once dismissed as “junk”, transposable elements have recently gained recognition for their regulatory roles, especially in the brain. During development, circulating androgens promote proper morphological development of hippocampal neurons. We and others have shown that murine B2 SINE RNA is a regulator in the rodent hippocampus. It is unknown, however, if B2 is necessary for the proper development of hippocampal neurons. This dissertation investigates the role of murine B2 in the development of primary hippocampal neurons in combination with androgen treatment. We first examined the role of ALU SINE and androgen receptor in a prostate cancer cell model and found …

Rod Photoreceptor Regeneration In A Zebrafish Model With Retinitis Pigmentosa, Eyad Shihabeddin

Dissertations and Theses (Open Access)

A cellular hallmark of inherited retinal degenerative diseases is progressive loss of photoreceptors until one is completely blind. Unlike mammalian models, Zebrafish have the ability to naturally regenerate their neurons after injury or disease is detected. We have generated a zebrafish model with the most common autosomal dominant form of the inherited retinal degenerative disease known as Retinitis Pigmentosa. We utilize immunohistochemistry, single-cell RNA sequencing, several analysis tools, behavioral assays and oligonucleotides to characterize our zebrafish model and identify the transcription factors necessary for rod photoreceptor regeneration. We show that our zebrafish model has continuous degeneration and regeneration of rod …

Plasma S100Β Is A Predictor For Pathology And Cognitive Decline In Alzheimer’S Disease, Geetika Nehra, Bryan J. Maloney, Rebecca Smith, Wijitra Chumboatong, Erin L. Abner, Peter T. Nelson, Björn Bauer, Anika M. S. Hartz

UK CARES Faculty Publications

Background Blood–brain barrier dysfunction is one characteristic of Alzheimer’s disease (AD) and is recognized as both a cause and consequence of the pathological cascade leading to cognitive decline. The goal of this study was to assess markers for barrier dysfunction in postmortem tissue samples from research participants who were either cognitively normal individuals (CNI) or diagnosed with AD at the time of autopsy and determine to what extent these markers are associated with AD neuropathologic changes (ADNC) and cognitive impairment.

Methods We used postmortem brain tissue and plasma samples from 19 participants: 9 CNI and 10 AD dementia patients who …

Blood Biomarkers In Down Syndrome: Facilitating Alzheimer’S Disease Detection And Monitoring, Melissa E. Petersen, Lisi Flores-Aguilar, Elizabeth Head, Laia Montoliu-Gaya, Andre Strydom, Sarah E. Pape, Juan Fortea, Nicholas J. Ashton, Chinedu Udeh-Momoh, Sid E. O’Bryant, Dwight German, Florin Despa, Mark Mapstone, Henrik Zetterberg

Neurology Faculty Publications

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer’s Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work …

Investigating Tumor Growth And Regulation In Supratentorial Ependymomas; The Impact Of Dlk1 And Egr1 Knockout, Om Sinojia

Honors Scholar Theses

Ependymomas (EPNs) are primary brain tumors that often arise from radial glial cells lining the ventricular system. Supratentorial ependymomas (ST-EPNs) are particularly aggressive, and understanding the molecular factors driving their growth is critical for developing targeted therapies. This study investigates the roles of DLK1 and EGR1, key regulators in cellular differentiation and tumorigenesis, in the development of ST-EPNs. We utilized genetically engineered mouse models to induce postnatal knockouts of DLK1 and EGR1 and evaluated tumor growth using histological and imaging techniques. Tumor area was quantified across multiple brain sections from both male and female mice. DLK1 knockout brains exhibited consistent …

Increased Neuroinflammation And Compromised Blood Brain Barrier In A Mouse Model Of Autism, Amani S. Ikram, Rekha Jagadapillai, Idil Tuncali, Gregory N. Barnes, Evelyne Gozal

The Cardinal Edge

No abstract provided.

Parallel Electrophysiological Abnormalities Due To Covid-19 Infection And To Alzheimer’S Disease And Related Dementia, Yang Jiang, Jennifer Neal, Pradoldej Sompol, Görsev Yener, Xianghong Arakaki, Christopher M. Norris, Francesca R. Farina, Agustin Ibanez, Susanna Lopez, Abdulhakim Al-Ezzi, Voyko Kavcic, Bahar Güntekin, Claudio Babiloni, Mihály Hajós

Neurology Faculty Publications

Many coronavirus disease 2019 (COVID-19) positive individuals exhibit abnormal electroencephalographic (EEG) activity reflecting “brain fog” and mild cognitive impairments even months after the acute phase of infection. Resting-state EEG abnormalities include EEG slowing (reduced alpha rhythm; increased slow waves) and epileptiform activity. An expert panel conducted a systematic review to present compelling evidence that cognitive deficits due to COVID-19 and to Alzheimer’s disease and related dementia (ADRD) are driven by overlapping pathologies and neurophysiological abnormalities. EEG abnormalities seen in COVID-19 patients resemble those observed in early stages of neurodegenerative diseases, particularly ADRD. It is proposed that similar EEG abnormalities in …

Characterizing Border Associated Macrophages During Spinal Cord Regeneration, Addison Vogt, Dana Shaw, Mayssa Mokalled

Undergraduate Research Symposium

The human central nervous system has limited regenerative ability, with injuries to the spinal cord (SC) often resulting in paralysis. Alternatively, zebrafish have enhanced innate regenerative capacity and regain full motor function following spinal cord injury (SCI). Immune activation following SCI is necessary to provide a permissive environment for tissue repair, but the immune pathways necessary for SC regeneration are not well characterized. In previous data, we have found that while immune activation is persistent into the chronic phases of SCI response in mammals, zebrafish achieve full immune clearance within 48 days post SCI. We hypothesize that one key distinction …

Cerebrovascular Reactivity Mri As A Biomarker For Cerebral Small Vessel Disease–Related Cognitive Decline: Multi-Site Validation In The Markvcid Consortium, Peiying Liu, Zixuan Lin, Kaisha Hazel, George Pottanat, Cuimei Xu, Dengrong Jiang, Jay J. Pillai, Emma Lucke, Christopher E. Bauer, Brian T. Gold, Steven M. Greenburg, Karl G. Helmer, Kay Jann, Gregory Jicha, Joel Kramer, Pauline Maillard, Rachel M. Mulavelil, Pavel Rodriguez, Claudia L. Satizabal, Kristin Schwab, Sudha Seshadri, Herpreet Singh, Ángel G. Velarde Dediós, Danny J. J. Wang, Rita R. Kalyani, Abhay Moghekar, Paul B. Rosenberg, Sevil Yasar, Marilyn Albert, Hanzhang Lu

Neurology Faculty Publications

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis.

METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes.

RESULTS: CVR …

Decentralized Clinical Trials For Medications To Reduce The Risk Of Dementia: Consensus Report And Guidance, Leanne Howard, Carla Abdelnour, Erin Abner, Ricardo F. Allegri, Hiroko H. Dodge, Serge Gauthier, Camilla M. Hoyos, Gregory Jicha, Patrick G. Kehoe, Catherine J. Mummery, Adesola Ogunniyi, Nikolaos Scarmeas, Xiaoying Chen, Jodie R. Titiner, Christopher R. Weber, Ruth Peters

Neurology Faculty Publications

INTRODUCTION: Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field.

METHODS: A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations.

RESULTS: Overall, the recommendations support the delivery of decentralized trials in dementia prevention …

Towards A New Role Of Mitochondrial Hydrogen Peroxide In Synaptic Function, Cliyahnelle Z. Alexander

Student Theses and Dissertations

Aerobic metabolism is known to generate damaging ROS, particularly hydrogen peroxide. Reactive oxygen species (ROS) are highly reactive molecules containing oxygen that have the potential to cause damage to cells and tissues in the body. ROS are highly reactive atoms or molecules that rapidly interact with other molecules within a cell. Intracellular accumulation can result in oxidative damage, dysfunction, and cell death. Due to the limitations of H₂O₂ (hydrogen peroxide) detectors, other impacts of ROS exposure may have been missed. HyPer7, a genetically encoded sensor, measures hydrogen peroxide emissions precisely and sensitively, even at sublethal levels, during …

Biophysical Model Of Retraction Motor Neurons And Their Modification By Operant Conditioning, Maria Rasheed

Dissertations and Theses (Open Access)

Operant conditioning (OC) is a form of associative learning in which an animal modifies its behavior based on the consequences that follow that behavior. Despite its ubiquity, the underlying mechanisms of OC are poorly understood. Insights into the mechanisms of OC can be obtained by studying Aplysia feeding behavior as it can be modified by OC. This behavior is mediated by a central pattern generator (CPG) network in the buccal ganglia that contains a relatively small number of neurons. This CPG generates rhythmic motor patterns (BMPs) that move food into the gut by closing a tongue-like structure (i.e., radula) during …

Development Of Vasculature Patterns In A Mouse Model Of Supratentorial Ependymoma, Jackson Ayers

Honors Scholar Theses

Supratentorial Ependymoma (ST-EPN) is a subtype of ependymoma, a primary solid tumor found throughout the nervous system. ST-EPN are most commonly caused by an oncogenic fusion between the zinc finger gene ZFTA and the RELA, and this distinct ependymoma subtype is readily modeled in mice by conditional expression of ZFTA-RELA in radial glial cells. ST-EPN are known to have a distinctive arrangement of tumor cells and vasculature forming pseudo-rosettes in which polarized tumor cells surround blood vessels within the tumors. It is not known how these pseudo-rosettes or the tumor vasculature form and develop in ST-EPN, so in this study …

Exploring The Developmental Effects Of Antidepressants In Caenorhabditis Elegans, Alexandra Van Stone

Annual Research Symposium

It is so important to explore the potential side effects of antidepressants especially if these side effects could lead to a future detriment to an individual’s financial and social well-being. A better understanding of these side effects in regards to human developmental issues is imperative considering issues related to mental health and depression affect a large percentage of the population. In this study, we tested if Caenorhabditis (C.) elegans could be a potential model organism to predict possible side effects associated with select antidepressants. Their developmental problems potentially encountered upon drug treatment may be encountered in humans.

Alzheimer’S Disease And Inflammatory Biomarkers Positively Correlate In Plasma In The Uk-Adrc Cohort, Kate E. Foley, Zachary Winder, Tiffany L. Sudduth, Barbara J. Martin, Peter T. Nelson, Gregory Jicha, Jordan P. Harp, Erica M. Weekman, Donna M. Wilcock

Neurology Faculty Publications

INTRODUCTION: Protein-based plasma assays provide hope for improving accessibility and specificity of molecular diagnostics to diagnose dementia. METHODS: Plasma was obtained from participants (N = 837) in our community-based University of Kentucky Alzheimer’s Disease Research Center cohort. We evaluated six Alzheimer’s disease (AD)- and neurodegeneration-related (Aβ40, Aβ42, Aβ42/40, p- tau181, total tau, and NfLight) and five inflammatory biomarkers (TNF𝛼, IL6, IL8, IL10, and GFAP) using the SIMOA-based protein assay platform. Statistics were performed to assess correlations. RESULTS: Our large cohort reflects previous plasma biomarker findings. Relationships between biomarkers to understand AD–inflammatory biomarker correlations showed significant associations between AD and inflammatory …

Utilizing Ai Integrated Neuroimaging Technology To Expand Upon Machine Learning In Positron Emission Tomography Technology With The Aim Of Detecting Amyloid Beta Biomarkers Early In The Onset Of Alzheimer's., Ethan S. Terman

Undergraduate Research Posters

Early intervention in Alzheimer's is vital for treatment. The earlier a professional can detect symptoms and make a diagnosis the earlier a prognosis can be implemented. With the prevalence of data in our day-to-day world combined with Artificial intelligence (AI), utilizing both for machine learning can pave the way for more accurate and efficient detection of Alzheimer's and other neurodegenerative diseases. AI combined with Machine learning (ML) increases diagnostic efficiency and reduces human errors, making it a valuable resource for physicians and clinicians alike. With the increasing amount of data processing and image interpretation required, the ability to use AI …

Different Cohort, Disparate Results: Selection Bias Is A Key Factor In Autopsy Cohorts, Kathryn Gauthreaux, Walter A. Kukull, Karin B. Nelson, Charles Mock, Yen-Chi Chen, Kwun C. G. Chan, David W. Fardo, Yuriko Katsumata, Erin L. Abner, Peter T. Nelson

Neurology Faculty Publications

INTRODUCTION: Research-oriented autopsy cohorts provide critical insights into dementia pathobiology. However, different studies sometimes report disparate findings, partially because each study has its own recruitment biases. We hypothesized that a straightforward metric, related to the percentage of research volunteers cognitively normal at recruitment, would predict other inter-cohort differences.

METHODS: The National Alzheimer’s Coordinating Center (NACC) provided data on N = 7178 autopsied participants from 28 individual research centers. Research cohorts were grouped based on the proportion of participants with normal cognition at initial clinical visit.

RESULTS: Cohorts with more participants who were cognitively normal at recruitment contained more individuals who …

Cognitive Decline, Aβ Pathology, And Blood–Brain Barrier Function In Aged 5xfad Mice, Geetika Nehra, Sasivimon Promsan, Ruedeemars Yubolphan, Wijitra Chumboatong, Pornpun Vivithanaporn, Bryan J. Maloney, Anusorn Lungkaphin, Bjoern Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background

Patients with Alzheimer’s disease (AD) develop blood–brain barrier dysfunction to varying degrees. How aging impacts Aβ pathology, blood–brain barrier function, and cognitive decline in AD remains largely unknown. In this study, we used 5xFAD mice to investigate changes in Aβ levels, barrier function, and cognitive decline over time.

Methods

5xFAD and wild-type (WT) mice were aged between 9.5 and 15.5 months and tested for spatial learning and reference memory with the Morris Water Maze (MWM). After behavior testing, mice were implanted with acute cranial windows and intravenously injected with fluorescent-labeled dextrans to assess their in vivo distribution in the …

Oxidative Stress Alters Mitochondrial Homeostasis In Isolated Brain Capillaries, Gopal V. Velmurugan, Hemendra J. Vekaria, Anika M. S. Hartz, Björn Bauer, William Brad Hubbard

Markey Cancer Center Faculty Publications

Background

Neurovascular deficits and blood-brain barrier (BBB) dysfunction are major hallmarks of brain trauma and neurodegenerative diseases. Oxidative stress is a prominent contributor to neurovascular unit (NVU) dysfunction and can propagate BBB disruption. Oxidative damage results in an imbalance of mitochondrial homeostasis, which can further drive functional impairment of brain capillaries. To this end, we developed a method to track mitochondrial-related changes after oxidative stress in the context of neurovascular pathophysiology as a critical endophenotype of neurodegenerative diseases.

Methods

To study brain capillary-specific mitochondrial function and dynamics in response to oxidative stress, we developed an ex vivo model in which …

Role Of The Anti-Viral Immune Response In Neural Cell Modulation And Neurological Sequelae Of Childhood Viral Infections, Yashika Kamte

Electronic Theses and Dissertations

Viral infections of the central nervous system (CNS) often result in neurological sequelae and are considered a risk factor for the development of neurological disease. Moreover, the outcomes of a viral infection are largely dependent on the age of the host, with younger hosts developing more profound neuropathology. Perhaps the developing brain coupled with an immature immune system contributes to worse outcomes in the very young. Children suffering from brain infections are more prone to develop enduring neurological impairments even after recovery from the infection. Although majority of the brain growth occurs in utero, neurodevelopment continues throughout the juvenile …

Proteasome Inhibition Protects Blood–Brain Barrier P-Glycoprotein And Lowers Aβ Brain Levels In An Alzheimer’S Disease Model, Milica Vulin, Yu Zhong, Bryan J. Maloney, Björn Bauer, Anika M. S. Hartz

Markey Cancer Center Faculty Publications

Background Loss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade®; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo.

Methods We treated hAPP mice with …

Changes In The Epigenetic Landscape Of Oligodendrocyte Progenitor Cells With Time, David K. Dansu

Dissertations, Theses, and Capstone Projects

Most neonatal oligodendrocyte progenitors (nOPCs) give rise to myelinating oligodendrocytes during development, while a proportion are retained as proliferative undifferentiated cells in the adult brain (aOPCs). Previous studies have reported distinct properties for those two populations but the molecular mechanisms underlying these intrinsic differences are not well understood. Using RNA-sequencing and unbiased histone proteomics analysis, we identify transcripts and histone marks that are higher in aOPCs than nOPCs. The genome-wide ChIP-sequencing analysis of chromatin from aOPCs compared to nOPCs detects greater occupancy of the H4K8ac mark at loci corresponding to the higher transcript levels of oligodendrocyte-specific transcription factors and lipid …

Novel Insights Into Oligodendrocyte Biology From Developmental Myelination Studies In Autophagy Deficient Mice And Analysis Of Oligodendrocyte Translatome Response To Contusive Spinal Cord Injury., Michael David Forston

Electronic Theses and Dissertations

Loss of myelin causes severe neurological disorders and functional deficits in white matter injuries (WMI) such as traumatic spinal cord injury (SCI). This dissertation is focused on autophagy in OL development and the OL translatome after SCI. Chapter I describes the history of myelin, OL development, and their involvement in neurodegenerative diseases and SCI. The proteostasis network, in particular autophagy, and its contributions to white matter pathology is discussed. It concludes examining advantages and disadvantages of unbiased omics tools, like RiboTag, to study transcriptional/translational landscapes after SCI. Chapter II focuses on autophagy in OPC/OL differentiation, survival, and proper myelination in …

Microglia Refine Early Multisensory Circuits In The Lateral Cortex Of The Inferior Colliculus In A Complement-Dependent Manner, Shaida Hamidi

Masters Theses, 2020-current

Microglia cells (MGCs), the resident macrophage of the brain, play a pivotal role in synaptic pruning of newly established circuits during early critical periods. Classical complement cascade signaling enables MGCs to identify unnecessary or underutilized contacts and specifically target them for removal and subsequent degradation. Such recognition and engulfment behaviors require receptor-ligand interactions, whereby “eat me” tags (complement component 3, C3) bind their cognate receptor (complement receptor 3, CR3) expressed on MGCs. Compromised complement signaling in certain systems results in under-pruning or unrefined map configurations, and is thought perhaps to underlie certain autism-related behavioral phenotypes (e.g. sensory hypersensitivities, decreased social …

Transcriptional Regulation Of Stem Cell Function In The Drosophila Central Nervous System, Amalia S. Parra

Biology ETDs

Development of multicellular organisms depends on coordination of various molecular mechanisms to ensure proper tissue size and structure. This is accomplished through intrinsic and extrinsic cues that regulate cell growth and proliferation both spatially and temporally. These well-coordinated signals are present from early developmental stages and remain active throughout development to ensure tissue structure is appropriate for function. This is particularly important in early cell types that form specialized lineages such as stem cells or those found throughout the body such as epithelia. While much progress has been made in understanding growth regulatory mechanisms, several fundamental aspects remain unknown. This …

Metoprolol Disrupts Sterol Biosynthesis Through Inhibition Of 7-Dehydrocholesterol Reductase (Dhcr7), Luke B. Allen

Theses & Dissertations

Cholesterol is essential for life. It is particularly important in the brain as it relies on de novo synthesis of cholesterol following the formation of the blood brain barrier (BBB). As such, disrupting sterol biosynthesis during neurodevelopment can have devastating outcomes. The most common post-lanosterol sterol biosynthesis disorder, Smith-Lemli-Opitz Syndrome, arises from a faulty DHCR7 enzyme. DHCR7 has also been shown to be inhibited by several psychotropic medications. Here we assess six beta-blockers and their effects on sterol biosynthesis in vitro. Two beta-blockers, metoprolol and nebivolol strongly inhibit DHCR7 in four separate in vitro models of both mouse and …

Med12 Is A Critical Regulator Of Neural Crest Lineage And Nervous System Myelination, Fatma Betul Aksoy Yasar

Dissertations and Theses (Open Access)

The Mediator complex (MED) is a multi-subunit protein complex integral to the eukaryotic transcription machinery. MED12 is a Cdk8- regulatory kinase module subunit directly implicated in human disease and is genetically altered in neurological disease and cancer. Numerous attempts at generating an in vivo system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of Med12 gene. To understand the cellular and molecular processes associated with its role in disease, we generated multiple mouse models with targeted depletion of MED12 in distinct cellular lineages. Our genetically engineered models with induced and conditional …