Med12 Is A Critical Regulator of Neural Crest Lineage and Nervous System Myelination

<p>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<em> in vivo</em> system to study the role of Med12 failed due to embryonic lethality associated with germline or developmental disruption of <em>Med12</em> 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 deletion of Med12 recapitulated clinical observations in XLID (X-Linked Intellectual Disability) patients with Med12 loss-of-function mutations. In the present study, we establish the role of Med12 in 1) <em>de novo</em> myelin synthesis in the central nervous system, 2) myelin maintenance in the adult peripheral nervous system, and finally, 3) pigmentation ability of hair melanocytes. Our models provide novel molecular functions and downstream targets of Med12, with a special emphasis on cells of neural crest origin. Moreover, our models constitute versatile <em>in vivo</em> tools for future studies by reliably modeling a variety of pathologies presented in multiple neurological syndromes, including but not limited to developmental intellectual disability syndromes, demyelination-induced peripheral neuropathies, and depigmentation disorders.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• AKSOY YASAR, FATMA BETUL
• <p>0000-0002-9841-7116</p>

Contributors dc:contributor

• Jian Hu, PhD
• Ambro Van Hoof, PhD
• Juan Fueyo, MD

• MED12
• Mediator complex
• Myelin
• XLID
• Demyelination
• Peripheral Nervous System
• Central Nervous Sytem
• CNS
• PNS
• Melanocytes
• Schwann Cells
• Biology
• Cell and Developmental Biology
• Congenital, Hereditary, and Neonatal Diseases and Abnormalities
• Developmental Neuroscience
• Disease Modeling
• Genetics
• Molecular and Cellular Neuroscience
• Nervous System Diseases
• Neuroscience and Neurobiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1231

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2288