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1.  Stem Cells Expanded from the Human Embryonic Hindbrain Stably Retain Regional Specification and High Neurogenic Potency 
The Journal of Neuroscience  2013;33(30):12407-12422.
Stem cell lines that faithfully maintain the regional identity and developmental potency of progenitors in the human brain would create new opportunities in developmental neurobiology and provide a resource for generating specialized human neurons. However, to date, neural progenitor cultures derived from the human brain have either been short-lived or exhibit restricted, predominantly glial, differentiation capacity. Pluripotent stem cells are an alternative source, but to ascertain definitively the identity and fidelity of cell types generated solely in vitro is problematic. Here, we show that hindbrain neuroepithelial stem (hbNES) cells can be derived and massively expanded from early human embryos (week 5–7, Carnegie stage 15–17). These cell lines are propagated in adherent culture in the presence of EGF and FGF2 and retain progenitor characteristics, including SOX1 expression, formation of rosette-like structures, and high neurogenic capacity. They generate GABAergic, glutamatergic and, at lower frequency, serotonergic neurons. Importantly, hbNES cells stably maintain hindbrain specification and generate upper rhombic lip derivatives on exposure to bone morphogenetic protein (BMP). When grafted into neonatal rat brain, they show potential for integration into cerebellar development and produce cerebellar granule-like cells, albeit at low frequency. hbNES cells offer a new system to study human cerebellar specification and development and to model diseases of the hindbrain. They also provide a benchmark for the production of similar long-term neuroepithelial-like stem cells (lt-NES) from pluripotent cell lines. To our knowledge, hbNES cells are the first demonstration of highly expandable neuroepithelial stem cells derived from the human embryo without genetic immortalization.
PMCID: PMC3721847  PMID: 23884946
2.  Genetic variation in FGF20 modulates hippocampal biology 
We explored the effect of Single Nucleotide Polymorphisms (SNPs) in the Fibroblast Growth Factor 20 gene (FGF20) associated with risk for Parkinson’s disease (PD) on brain structure and function in a large sample of healthy young-adult human subjects and also in elderly subjects to look at the interaction between genetic variations and age (N = 237, 116 men, 18–87 years). We analyzed high resolution anatomical magnetic resonance images using voxel-based morphometry, a quantitative neuroanatomical technique. We also measured FGF20 mRNA expression in post-mortem human brain tissue to determine the molecular correlates of these SNPs (N = 108, 72 men, 18–74 years). We found that the T allele carriers of rs12720208 in the 3’ UTR had relatively larger hippocampal volume (p = 0.0059), diminished verbal episodic memory (p = 0.048) and showed steeper decreases of hippocampal volume with normal ageing (p = 0.026). In post-mortem brain, T allele carriers had greater expression of hippocampal FGF20 mRNA (p = 0.037), consistent with a previously characterized microRNA mechanism. The C allele matches a predicted miR-433 microRNA binding domain, whereas the T allele disrupts it, resulting in higher FGF20 protein translation. The strong FGF20 genetic effects in hippocampus are presumably mediated by activation of the FGF receptor 1 (FGFR1), which is expressed in mammalian brain most abundantly in the hippocampus. These associations, from mRNA expression to brain morphology to cognition and an interaction with ageing, confirm a role of FGF20 in human brain structure and function during development and aging.
PMCID: PMC2909689  PMID: 20427658
FGF20; Genetic; Voxel-Based Morphometry; Neuroimaging; MRI; Hippocampus
3.  Provisional hypotheses for the molecular genetics of cognitive development: Imaging genetic pathways in the anterior cingulate cortex 
Biological psychology  2007;79(1):23-29.
Brain imaging genetic research involves a multitude of methods and spans many traditional levels of analysis. Given the vast permutations among several million common genetic variants with thousands of brain tissue voxels and a wide array of cognitive tasks that activate specific brain systems, we are prompted to develop specific hypotheses that synthesize converging evidence and state clear predictions about the anatomical sources, magnitude and direction (increases vs. decreases) of allele- and task-specific brain activity associations. To begin to develop a framework for shaping our imaging genetic hypotheses, we focus on previous results and the wider imaging genetic literature. Particular emphasis is placed on converging evidence that links system-level and biochemical studies with models of synaptic function. In shaping our own imaging genetic hypotheses on the development of Attention Networks, we review relevant literature on core models of synaptic physiology and development in the anterior cingulate cortex.
PMCID: PMC2570040  PMID: 18261834
4.  The foxa2 Gene Controls the Birth and Spontaneous Degeneration of Dopamine Neurons in Old Age  
PLoS Biology  2007;5(12):e325.
Parkinson disease affects more than 1% of the population over 60 y old. The dominant models for Parkinson disease are based on the use of chemical toxins to kill dopamine neurons, but do not address the risk factors that normally increase with age. Forkhead transcription factors are critical regulators of survival and longevity. The forkhead transcription factor, foxa2, is specifically expressed in adult dopamine neurons and their precursors in the medial floor plate. Gain- and loss-of-function experiments show this gene, foxa2, is required to generate dopamine neurons during fetal development and from embryonic stem cells. Mice carrying only one copy of the foxa2 gene show abnormalities in motor behavior in old age and an associated progressive loss of dopamine neurons. Manipulating forkhead function may regulate both the birth of dopamine neurons and their spontaneous death, two major goals of regenerative medicine.
Author Summary
The restoration of dopamine neurons is a major focus of stem cell biology and regenerative medicine. The gradual loss of these neurons is a hallmark of Parkinson disease. Dopamine neurons in the midbrain convey important sensory and motor functions to the forebrain. We show that the transcription factor FOXA2 plays a central role in the birth and death of dopamine neurons in the midbrain. By defining their precursors in the ventral midbrain, we show that dopamine neurons are derived from organizer cells in the floor plate (the ventral cells of the neural tube, the embryonic foundation of the central nervous system). We also show that FOXA2 specifies the floor plate and induces the birth of dopamine neurons. Mice with only a single copy of the foxa2 gene acquire motor deficits and a late-onset degeneration of dopamine neurons. This spontaneous cell death preferentially affects neurons associated with Parkinson disease. This work provides new strategies to generate neurons in the laboratory and to block their death in old age.
The connection between development and neurodegeneration is emphasized via a new mouse knockout of a transcription factor that is critical for dopamine neuron specification, which produces a late-onset, asymmetric degenerative condition in a manner very similar to human Parkinson disease.
PMCID: PMC2121110  PMID: 18076286

Results 1-4 (4)