Alvarez-Buylla Laboratory

The cellular architecture of the mouse SVZ by electron microscopy.

The Alvarez-Buylla Lab is interested in the function and regulation of neural stem cells in the mammalian brain.  We address questions about the mechanisms of neuronal birth, migration, and differentiation, and how neural stem cells or their immediate progeny may be related to brain tumor initiation.  The subventricular zone (SVZ), the most extensive germinal niche in the adult mammalian brain, contains large numbers of neural stem cells that can generate new neurons and glial cells throughout life.  By means of chain migration, young neurons born in the SVZ reach the olfactory bulb in the mouse brain, where they become fully integrated into functional circuits.  We have identified the neural stem cells in the SVZ as a subpopulation of astrocytes.  More recently, we found that adult neural stem cells are heterogeneous and that particular types of neurons are derived from progenitors within specific locations of the mouse SVZ.

We are investigating the properties and ontogeny of astrocytes that function as stem cells in the rodent and human brain, and the regulation of their proliferation.  We are also interested in the mechanism of cell migration in the adult brain.  How do cells migrate and orient during journeys through the very complex terrain of the adult brain?  Once young neurons reach their destination, they need to integrate into neural circuits that are already functional.  How is this accomplished?  How do these new neurons contribute to plasticity without disturbing circuits that are already active?  These are some of the questions that drive our research.  Below, three lines of research in the laboratory are tightly related to human disease. 

Current Research Projects:

Are Adult Brain Progenitors a Source of Brain Tumors?

Artist's depiction of mouse SVZ

Primary tumors of the central nervous system occur with high incidence in humans and remain clinically intractable. Since the 1940s, it has been suspected that the adult mammalian SVZ may be a source of astrocytomas. We are studying whether the stem cells or transit amplifying cells we have identified in the SVZ give rise to adult brain tumors. We are studying the molecular pathways through which neurogenesis is normally regulated, and how deregulation could result in aberrant growth and possible initiation of tumor formation. Along these lines, we are studying the role of primary cilia in postnatal neural progenitor cell specification and tumor growth.

A Germinal Layer in the Adult Human Brain

GFAP-positive periventricular ribbon of astrocytes in adult human SVZ.

The SVZ has been fully characterized only in rodents, macrosmatic animals with relatively large olfactory bulbs.  We are characterizing the analogous structure in postnatal human brains.  It has been proposed that the SVZ may be an important source of neural stem cells for future therapies to treat neurodegenerative diseases, but its role in humans remains largely unknown.  The clinical implications of stem cells in the postnatal brain range beyond that of their regenerative potential.  We are conducting a detailed analysis of the development of human SVZ that will: (1) define its organization; (2) characterize its cytoarchitecture and ultrastructure; (3) identify the target(s), mechanism(s), and extent of human neuroblast migration; (4) isolate the population of SVZ stem cells; and (5) determine the development of this germinal layer through late fetal, neonatal, and postnatal stages.

Neural replacement in the Cortex and Striatum

Transplanted GABAergic neurons (green) migrate and survive in the recipient brain.

The above studies of the SVZ have demonstrated that migration and integration of new neurons can take place in juvenile and adult mammalian brain.  This suggests new strategies for brain repair.  However, under normal conditions in mouse brains, postnatal SVZ neuronal precursors migrate and integrate only in the olfactory bulb.  This is a limitation for the use of these precursors for brain repair.  In collaboration with other laboratories at UCSF, we study populations of GABAergic inhibitory interneuron progenitors that can migrate and integrate into adult neural circuits outside the olfactory bulb.  We have identified precursors in the ventral forebrain of the developing embryo that migrate long distances and fully develop into inhibitory local circuit neurons in the postnatal brain.  These cells disseminate and integrate particularly well in postnatal cortex where they increase local inhibition.  These cells could be useful in the treatment of epilepsy and Parkinson's disease.  Ongoing studies are using animal models for these diseases to determine the effects of increasing local inhibition.  

The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF

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