Neural Stem Cells Lend The Brain A Surprising Capacity For Self-repair

The researchers found that mice whose brains were severely damaged by loss of the genes "Numb" and "Numblike" in one region just after birth showed substantial mending within weeks. They attributed that repair to neural stem cell "escapees" that had somehow retained or restored the genes' activity and, with it, their regenerative potential.

"At two weeks, the knockout animals' brains had developed a big hole," said Yuh-Nung Jan, a Howard Hughes Medical Institute investigator at the University of California, San Francisco. "We thought that the mice would not live long, but by four weeks, the hole was largely repaired and the animals survived.

"It was a big surprise. It was not known that the brain has this kind of ability to repair itself."

Jan and his colleagues first discovered Numb in the fruit fly Drosophila more than 10 years ago. The gene was found by them and others to play a role in determining the fate of neuroblasts, cells that develop into neurons or other support cells in the insects' brains. Later, researchers found two functionally related mammalian proteins, dubbed Numb and Numblike, to be critical in the development of neurons in embryonic mice.

To investigate the genes' role after birth, Jan's team developed mice in which Numb and Numblike could be turned off only in a portion of the brain termed the subventricular zone (SVZ) when they administered a particular drug. The SVZ is known to be a site, or niche, that contains neural stem cells after birth.

In newborn mice, loss of the genes left the SVZ "greatly disturbed," Jan said.

Their results indicated that Numb and Numblike have two important functions, namely a role in the survival of neuroblasts and an unexpected role in maintaining the cellular wall that lines the ventricular region of the brain in which the SVZ resides. Without the normal complement of genes, that wall "disintegrated," he said, leaving holes in the brain.

Surprisingly, they reported, the ventricular damage was eventually repaired. SVZ reconstitution and remodeling of the ventricular wall was driven by progenitor cells that escaped Numb deletion, they found.

"Although the exact mechanisms are still being worked upon, these observations raise the possibility that postnatal neurogenesis can one day be used to repair brain damage," the researchers concluded.

"Our results here show that self-repair and local remodeling can indeed happen along the brain's lateral ventricular wall, and further insights into this process should shed light on whether SVZ neural stem cells participate in stroke/trauma-induced brain remodeling and postnatal/adult brain tumor formation. Furthermore, understanding how the SVZ cells participate in local repair should help bring us closer to the goal of using neural stem cells as therapeutic agents in neurodegenerative diseases."

The researchers include Chay T. Kuo, Denan Wang, Lily Y. Jan, and Yuh-Nung Jan of Howard Hughes Medical Institute and University of California, San Francisco in San Francisco, CA; Zaman Mirzadeh and Arturo Alvarez-Buylla of University of California, San Francisco in San Francisco, CA; Mario Soriano-Navarro and Jose Garcia-Verdugo of Principe Felipe-Universidad de Valencia in Valencia, Spain; Mladen Rašin and Nenad Šestan of Yale University School of Medicine in New Haven, CT; Jie Shen of Brigham and Women's Hospital and Harvard Medical School in Boston, MA.

This work was supported by National Institutes of Health Grant 5 R01 NS047200. C.T.K. is a Calif. Inst. of Regenerative Medicine postdoctoral scholar. Y.N.J. and L.Y.J. are Howard Hughes Medical Institute investigators.

Kuo et al.: "Postnatal Deletion of Numb/Numblike Reveals Repair and Remodeling Capacity in the Subventricular Neurogenic Niche." Publishing in Cell 127, 1253--1264, December 15, 2006. DOI 10.1016/j.cell.2006.10.041 http://www.cell.com