THE ROLE OF VITAMIN B12-DEPENDENT METABOLIC PATHWAYS IN NEURAL CREST DEVELOPMENT

/ABSTRACT Neural crest cells (NCCs) comprise a multipotent population of cells that migrate throughout the vertebrate embryo and differentiate into a wide variety of cell types and tissues such as the enteric, autonomic, and peripheral nervous system; tissues of the adrenal gland, thyroid gland, heart, and eye; melanocytes of the skin; and craniofacial bone and cartilage. Therefore, disruptions in NCC specification, migration, and/or differentiation can affect many aspects of embryonic development leading to an array of debilitating congenital malformations collectively called neurocristopathies. Thus, our long-term goal is to define the cellular and molecular mechanisms governing NCC development leading to new therapeutic targets. In this proposal we aim to define the syndrome combined methylmalonic acidemia and homocystinuria, cblC-type (cblC) – an inborn error of cobalamin (vitamin B12) metabolism (IECM) – as also a neurocristopathy impacting mammalian development. CblC is caused by mutation of the gene MMACHC, which encodes an enzyme essential for intracellular trafficking and metabolism of cobalamin into its active coenzyme states. Without active cobalamin, dependent metabolic pathways cannot function properly and consequently, severe neurodevelopmental defects, anemia, retinopathy, and other congenital disorders result. However, the specific contributions of each metabolic perturbation to the tissue-specific pathophysiology of cblC is largely unknown and there are no effective treatments for affected infants and children. In our preliminary studies, we discovered that Mmachc may play a role in neural crest development and thereby redefine cblC as a neurocristopathy. Therefore, this proposal aims to use novel mouse models of IECM to identify which specific cobalamin-dependent pathway, when disrupted, leads to neural crest developmental defects. We will also investigate whether modulation of the maternal environment can improve the phenotypic presentation of cblC defects in offspring. In total, these finding will shed much needed light on the pathophysiology of cblC and likely inform patient treatment. Project Number: 5R01HD116761-02 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Ross Poche | Institution: BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX | Award Amount: $534,899 | Activity Code: R01 | Study Section: Development - 2 Study Section[DEV2] View on NIH RePORTER: https://reporter.nih.gov/project-details/5R01HD11676102