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The UCSF Program
in Craniofacial and Mesenchymal Biology
FACULTY
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The Mammalian Forebrain
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The embryonic neural tube differentiates into diverse structures depending upon their spatial coordinates within the embryo. The forebrain, which is at the rostral end of the neural tube, differentiates into the cerebral cortex, the basal ganglia, and other components, each with distinct histologies and functions. Our laboratory is interested in elucidating the genetic programming that regulates regional specification and differentiation of the mammalian forebrain. We have identified several novel genes that are candidates for this regulation, and we are focusing on two types of transcription factors. One (Tbr-1) encodes a homologue of Brachyury that is expressed in the cerebral cortex, while the other (Dlx) encodes a homeodomain that is expressed in the primordia of the basal ganglia. Analysis of the expression of these and related genes has proven to be a useful method to define subdivisions of the forebrain. These studies have led us to propose that the forebrain is subdivided by longitudinal and transverse boundaries, and thereby has a neuromeric organization. We are continuing to investigate the inductive mechanisms that pattern the neural plate and neural tube. To determine the function of the candidate regulatory genes, we have generated mice that have loss-of-function and gain-of-function mutations. To study development of the basal ganglia, we are analyzing the phenotypes of mice that lack function of several homeobox genes (Dlx-1, Dlx-2, Dlx-5, and Nkx-2.1); to study development of the cerebral cortex, we are analyzing the phenotypes of mice that have mutations in other transcription factors (Tbr-1, Emx-1, and Gbx-2).
These investigations have demonstrated the role of specific transcription factors in regulating neuronal specification, differentiation, migration and axon growth. In the long term, we seek to understand the hierarchy of regulatory genes that orchestrate development of the forebrain, and we have begun to search for the proteins that regulate Dlx expression, the targets of the DLX proteins, and proteins that interact with the DLX proteins and modulate their transcriptional activity. We would eventually like to integrate these findings to improve our knowledge of human neurodevelopmental disorders.
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Selected Publications
Cobos I, Broccoli V, Rubenstein JL (2005) The vertebrate ortholog of Aristaless is regulated by Dlx genes in the developing forebrain. J Comp Neurol 483(3): 292-303.
Jones EG, Rubenstein JL (2004) Expression of regulatory genes during differentiation of thalamic nuclei in mouse and monkey. J Comp Neurol 477:55-80.
Depew, M.J., Lufkin, T., and Rubenstein, J.L. (2002) Specification of jaw subdivisions by DIx genes. Science 298:381-385.
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Osteoblast depositing
bone matrix |
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