Research in the Palmer Lab
Human brain development and maintenance is orchestrated by a complex interaction of genetic and environmental factors. Our research examines how neural stem cells respond to these cues to add and integrate new neurons into functional circuits.
NEURAL STEM CELLS IN DEVELOPMENT: Our studies of neurogenesis in the developing brain focus on the influence of maternal health or illness on fetal brain development. In mice, even mild maternal illness during early pregnancy can alter stem cell activity in the developing fetal brain. This leads to subtle changes in social behavior and cognition reminiscent of autism. Prior epidemiological studies have noted that autoimmune events, allergies, or infections during pregnancy may increase the risk of autism in the child. Our ongoing research focuses on genetic risk factors for autism that may exacerbate the effects of maternal illness on fetal brain development.
NEURAL STEM CELLS IN THE ADULT: Our studies of stem cells in the adult focus on the hippocampus, one of the few areas where neurogenesis naturally continues throughout life. We have found that this region contains a unique arrangement of cells and signals that instruct stem cells to generate new neurons. Our goal is to determine if manipulating these signals might augment neurogenesis and enhance stem cell mediated CNS repair.
STEM CELLS TO STUDY CNS INJURY AND DISEASE: Using information gained from studying neural stem cells in development and in the adult, we have been able to reconstruct the conditions of neurogenesis in the Petri dish. We are now able to use human embryonic stem cells and non-embryonic induced pluripotent stem cells to generate several types of human neurons, including those lost in Parkinsons disease.
Pluripotent stem cells from patients who suffer from neurological disorders promise to be fundamentally important tools for identifying disease mechanisms or for providing neurons for repair. Understanding how new neurons are produced, and more importantly integrated, is critical for guiding efforts to restore function. With sufficient insights into the native control of neurogenesis, it may be possible to ameliorate the devastating effects of neurodevelopmental disease, injury, or aging-related disorders such as Parkinsons or Alzheimers disease.
A Knockin Reporter Allows Purification and Characterization of mDA Neurons from Heterogeneous Populations
2017; 18 (10): 2533-2546
Generation of midbrain dopaminergic (mDA) neurons from human pluripotent stem cells provides a platform for inquiry into basic and translational studies of Parkinson's disease (PD). However, heterogeneity in differentiation in vitro makes it difficult to identify mDA neurons in culture or in vivo following transplantation. Here, we report the generation of a human embryonic stem cell (hESC) line with a tyrosine hydroxylase (TH)-RFP (red fluorescent protein) reporter. We validated that RFP faithfully mimicked TH expression during differentiation. Use of this TH-RFP reporter cell line enabled purification of mDA-like neurons from heterogeneous cultures with subsequent characterization of neuron transcriptional and epigenetic programs (global binding profiles of H3K27ac, H3K4me1, and 5-hydroxymethylcytosine [5hmC]) at four different stages of development. We anticipate that the tools and data described here will contribute to the development of mDA neurons for applications in disease modeling and/or drug screening and cell replacement therapies for PD.
View details for DOI 10.1016/j.celrep.2017.02.023
View details for Web of Science ID 000397329500020
View details for PubMedID 28273465
Phosphorylation of aB-crystallin supports reactive astrogliosis in demyelination.
Proceedings of the National Academy of Sciences of the United States of America
2017; 114 (9): E1745-E1754
The small heat shock protein αB-crystallin (CRYAB) has been implicated in multiple sclerosis (MS) pathogenesis. Earlier studies have indicated that CRYAB inhibits inflammation and attenuates clinical disease when administered in the experimental autoimmune encephalomyelitis model of MS. In this study, we evaluated the role of CRYAB in primary demyelinating events. Using the cuprizone model of demyelination, a noninflammatory model that allows the analysis of glial responses in MS, we show that endogenous CRYAB expression is associated with increased severity of demyelination. Moreover, we demonstrate a strong correlation between the expression of CRYAB and the extent of reactive astrogliosis in demyelinating areas and in in vitro assays. In addition, we reveal that CRYAB is differentially phosphorylated in astrocytes in active demyelinating MS lesions, as well as in cuprizone-induced lesions, and that this phosphorylation is required for the reactive astrocyte response associated with demyelination. Furthermore, taking a proteomics approach to identify proteins that are bound by the phosphorylated forms of CRYAB in primary cultured astrocytes, we show that there is clear differential binding of protein targets due to the specific phosphorylation of CRYAB. Subsequent Ingenuity Pathway Analysis of these targets reveals implications for intracellular pathways and biological processes that could be affected by these modifications. Together, these findings demonstrate that astrocytes play a pivotal role in demyelination, making them a potential target for therapeutic intervention, and that phosphorylation of CRYAB is a key factor supporting the pathogenic response of astrocytes to oligodendrocyte injury.
View details for DOI 10.1073/pnas.1621314114
View details for PubMedID 28196893
View details for PubMedCentralID PMC5338510
- Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease CELL STEM CELL 2016; 19 (6): 709-724 Hide More
Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease.
Cell stem cell
Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro. Pathogenic LRRK2G2019S disrupts this function, delaying the arrest of damaged mitochondria and consequently slowing the initiation of mitophagy. Remarkably, partial reduction of Miro levels in LRRK2G2019S human neuron and Drosophila PD models rescues neurodegeneration. Miro degradation and mitochondrial motility are also impaired in sporadic PD patients. We reveal that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.
View details for DOI 10.1016/j.stem.2016.08.002
View details for PubMedID 27618216
View details for PubMedCentralID PMC5135570
- The Role of the Microenvironmental Niche in Declining Stem-Cell Functions Associated with Biological Aging COLD SPRING HARBOR PERSPECTIVES IN MEDICINE 2015; 5 (12) Hide More