Regulatory Pathway In Brain Development Possible Basis For Malformations

Bruce Hamilton, Ph.D., associate professor in the Department Medicine, and his colleagues have identified a genetic regulatory pathway that controls a neural precursor cell's decision to self-renew as a dividing precursor or differentiate into a non-dividing neuron. Cells that are unable to differentiate appropriately and continue to proliferate may give rise to brain cancers. On the other hand, cells that differentiate too soon or make too few cells can result in malformations of critical brain structures.

"Development of the brain requires intricate coordination to control the proliferation, differentiation, and connections among different groups of cells," said Hamilton. "We have found a gene in mice, mutated in one kind of malformation, which appears both to promote proliferation and to help coordinate differentiation of immature precursor cells."

The work in Hamilton's lab, led by UCSD Biomedical Sciences graduate students Wendy Alcaraz and David Gold, discovered a specific transcription factor called Zfp423. When Zfp423 is mutated in mice, developmental defects in the cerebellum occur that resemble Dandy-Walker malformations seen in human patients.

Dandy-Walker malformations occur in about one in 25,000 human births. Patients have a congenital malformation in the cerebellum, an area of the brain that controls movement, which can significantly slow motor development and cause progressive enlargement of the skull. Dandy-Walker malformation is frequently associated with disorders of other areas of the central nervous system and malformations of the heart, face, limbs, fingers and toes. Study of the Zfp423 mouse model in Hamilton's lab provides an important genetic clue in Dandy-Walker malformations, whose causes are not well understood.

"Loss of Zfp423 in mice results in diminished proliferation by precursor cells at a key time in the development of the cerebellum, resulting in its malformation," said Alcaraz.

The protein encoded by Zfp423 regulates the expression of other genes and is required for normal levels of proliferation by neural precursor cells in the cerebellum. This gene had previously been identified as a co-factor in two distinct signaling or regulatory pathways that mediate neuronal differentiation. The new work proposes that Zfp423 actually acts as a bridge between the two pathways.

"This means that external signals used in cell-cell communication could affect the developing neurons in ways we hadn't previously realized," Hamilton said. "In particular, cell lineage pathways that are often thought of as independent of signaling once they are initiated may really be under tight regulation by signaling-dependent pathways that compete with them for access to factors like Zfp423." He added that development of this mouse could lead to targeted therapies for some genetic brain disorders.

Additional contributors to this paper include Eric Raponi and Dorothy Concepcion of the UCSD Department of Medicine and Peter M. Gent, of the UCSD Biomedical Sciences Graduate Program. The research was funded in part by grants from the National Institutes of Health.