'American Association for the Advancement of Science (AAAS)'
Doi
Abstract
The brain, one of the most complex organs in the body, where an immense diversity of cell
states emerges from simple structure, where function arises from sets of regulatory principles
and pattern persist where individual cells do not. Revealing the regulatory underpinnings of
the brain, from unspecified cell states to diversity, is paramount for achieving a thorough
understanding of the development process and generating insight into the disease states of the
brain. This thesis is an exploration into how canonical regulatory factors and elements, such
as transcription factors and genes, lock a regulatory system in a multi-outcome network with
limited possible states.
The work in this thesis focuses on the oligodendrocyte lineage, a glial cell known for it’s
supportive role in the central nervous system, where it facilitates electrical transmission
through the enscheathment of axons. Oligodendrocytes (OLs) lie at the heart of multiple
sclerosis (MS), a disease where an immune response is mounted against myelin. As a
response, oligodendrocyte precursor cells (OPCs) move towards lesions and remyelinate
axons, however, this mechanism fails in later stages of the disease. Thus, an understanding to
how OPCs develop is vital to amelioration of the altered oligodendrocyte population.
In Paper I we reveal a previously underestimated heterogeneity within the oligodendrocyte
lineage in mouse. We show that OL maturation is an ongoing process, albeit, decreasing in
frequency with age. Furthermore, complex wheel training in mice revealed that the OLs
respond to this challenge through an increase in differentiation.
Paper II investigates the cellular response in the experimental autoimmune encephalomyelitis
(EAE) disease mouse model of MS, where we find a tailored response by the
resident OL population, changed from its normal transcriptional program, expressing a
spectrum of genes related to survival, immunological stimulation, phagocytosis, and active
differentiation. Furthermore, we provide evidence that OLs can elicit responses from T cells.
In Paper III we explore the different waves of OPC generation in the developing mouse
brain at embryonic day 13.5 and postnatal day 7. We show that recently Pdgfra expressing
cells at the E13.5 time point exhibit a multitude of patterning genes, and we show the
emergence of a possible OPC progenitor through the inclusion of a bridging E17.5 time point
population. This pre-OPC population is biased towards expressing glial and OL lineage
specifying genes such as Olig1, Olig2, Ptprz1, and Bcan. Furthermore, lineage tracing of
OPC developmental waves, shows no transcriptional differences, leading us to conclude that
OPCs are generally naïve to the time or region of specification.
In Paper IV we show that we are able to detect OPC formation in the developing human
forebrain. We detect OPCs at the earliest sampled time point post conception week 8. We
attempt to recover the path of OPC formation, and investigate the regulatory dynamics in the
specification of OPCs