- Developmental and Stem Cell Biology
- Cell and Molecular Biology
- Reproduction, Development and Genetics
- Integrative Physiology
- Adult Stem Cells
|Department||Department of Physiology, Anatomy and Genetics|
|College||St John's College|
The six layered mammalian cerebral cortex evolved with a huge increase in cortical neuronal populations, which had to be met with a corresponding increase of neurogenic compartments. In spite of the relatively constant number of neurons within a unit column of cerebral cortex and in spite of the relatively constant ratio between excitatory and inhibitory neurons in various species, there is a remarkable increase in the cortical surface and the number of cortical areas. This intensified the demand for the generation of both inhibitory and excitatory neuronal populations. Comparative studies of the embryonic neurogenic compartments are particularly interesting in understanding the developmental changes associated with the generation of interneurons and to excitatory cortical neurons. These studies revealed that the elaboration of mitotic compartments with various progenitor populations might have been the drive behind mammalian cortical evolution. We believe that rigorous analysis of the developmental neurobiology of the various progenitor populations in the cerebral cortex will not only help us the principles of cortical circuit formation, but also will eventually enable us to design cell replacement therapy in the brain.
Projects in our laboratory with relevance to the Oxford Stem Cell Institute include:
1: Comparative analysis of cortical progenitor populations in various vertebrates and the roles of non-coding and protein-coding genes in the evolutionary expansion of the cerebral cortex
Neural cells are born at different stages of embryonic development in spatially discrete compartments that are largely transient. The first compartment to appear, the ventricular zone (VZ) lines the ventricles and is composed of neurogenic radial glia and short progenitors. A secondary compartment, the subventricular zone (SVZ) arises from the VZ, and is comprised of gliogenic and neuronic progenitors. Pallial (dorsal) VZ and SVZ give rise to the cerebral cortex, whereas subpallial (ventral) VZ and SVZ’s give rise to basal ganglia and interneurons that migrate to cerebral cortex. Pallial and subpallial VZ and SVZ can be further subdivided into distinct compartments of transcription factor expression, which correspond to transient bulges in the subpallium; the lateral, medial, and caudal eminences. The embryonic SVZ expanded hugely during evolution and is a likely source of the preponderance of glia and interneurons in the human cortex.
Our group has compared the telencephalic proliferative compartments of (A) turtle, (B) chick, (C) marsupial, and (D) rat telencephali. Scale bars = 400 μm in A–C, 100 μm in D. Abbreviations: DVR: dorsal ventricular ridge; dCtx: dorsal cortex; GE: ganglionic eminence; Hyp: hyperpallium; LGE: lateral ganglionic eminence; MGE: medial ganglionic eminence; MP: mesopallium; NP: nidopallium; Sep: septum; Str: striatum. Note the increase of the abventricularly proliferating progenitor cells in the rat dortal cortex (dCtx) in D. From Abdel-Mannan, Cheung AF and Molnár (2008) Brain Res Bull. 75:398.
2: Neurovascular interactions during cortical neurogenesis, migration and differentiation.
There is evidence for interaction between the developing circulatory and nervous systems, with increasing relevance from a physiological and clinical perspective. Blood vessels provide a supporting niche in regions of adult neurogenesis. We are interested in the relation between cell divisions and blood vessel development in the embryonic telencephalon. We recently performed a systematic analysis of vascular development in the murine cortex and demonstrate that dividing cells, including Tbr2 positive intermediate progenitor cells are closer to the vasculature than expected from a random distribution. It appears that similarly to other neurogenic regions in the adult, the embryonic vascular niche might influence neural progenitor cells during telencephalic neurogenesis, neuronal migration and neurite extension, but the laminar phenotype of cell classes within the cortical plate have limited influence on the developing vasculature.
Coronal section through an E14.5 mouse dorsal cerebral cortex and hippocampus. The Tbr2 immunoreactive intermediate progenitors (red) in the subventricular zone (SVZ) are associated to the blood vessel plexi (green) in the developing cerebral cortex providing a vascular niche for the embryonic cell divisions (phospho-histone 3 immunoreactive, appear yellow) generating cortical neurons (Image from Kai Nie and Jamin De Proto, laboratory of ZM).
3: Cellular and molecular factors involved in the specification of cortical layer 5 projection neurons.
Layer V pyramidal neurons fall into two major classes that can be distinguished on the basis of their projection site, morphology and physiological properties in the adult. Although the two subtypes of layer V neurons are generated at the same time, within the same region of cortical germinal zone, their program of differentiation is different due to early molecular determinants during their last division. We are interested in the developmental sequence leading to target selection, somatodendritic differentiation and emergence of distinct physiological properties.
The diagram summarises the developmental sequence leading to target selection, somatodendritic differentiation and emergence of distinct physiological properties. Molnár Z and Cheung A.F.P. (2006) Neuroscience Research 55(2):105-115.
Sources of Funding
Zoltán Molnár obtained his M.D. (summa cum laude) at the Albert Szent-Györgyi Medical University, Szeged, Hungary where he started his residency in Neurological Surgery until he moved to Oxford in 1989. He obtained his D.Phil. at the University Laboratory of Physiology in the laboratory of C. Blakemore. His thesis on the "multiple mechanisms in the establishment of thalamocortical innervation" won the Rolleston Memorial Prize of Oxford and Cambridge Universities for 1994. He continued his work on cerebral cortical development at Oxford as an MRC training fellow and Junior Research Fellow at Merton College. He also investigated thalamocortical development working with E. Welker at the Institut de Biologie Cellulaire et de Morphologie, Université de Lausanne, Switzerland, and learned optical recording techniques to understand early functional thalamocortical interactions in the laboratory of K. Toyama at Kyoto Prefectural School of Medicine, Japan. In 1999 he was awarded the Krieg Cortical Kudos Cortical Explorer Prize of the American Anatomical Society's Cajal Club. He was appointed to a University Lecturer position at the Department of Human Anatomy and Genetics associated with a Tutorship at St John's College, Oxford from 2000. He was awarded the title Professor of Developmental Neuroscience in 2007.