As a mouse fetus develops in utero, it acquires a generousoversupply of neuronal cells. Later in gestation, as its brainand nervous system take shape, all of the excess neurons dieoff.An intricate complex of nerve growth factors (NGF) and theirreceptors monitors this process.These molecules ensure the survival of the neurons that willserve the animal after birth and throughout its life. When theyturn off, the surplus ones commit cell suicide (apoptosis).Most of the myriad cells in a mammal's body divide andreplace themselves as they age, but not neurons. They growold, all right, but don.t grow replacements. This neuronalsenescence, neurobiologists believe, helps account for somedisorders of human aging, notably Alzheimer's andParkinson's diseases.By studying the factors that control neuronal survival in theneonatal mammal, these scientists hope some day to developdrugs that can aid the survival and delay the die-off of neuronsdiminished by aging or damaged by trauma. Recombinantnerve growth factor (rNGF) is poised for clinical trials after atleast two companies, Alkermes Inc. and CytoTherapeuticsInc., last year demonstrated that they can administer the cell-saving molecule past the blood-brain barrier (See BioWorld,Jan. 15, 1993, p. 1 and Aug. 6, 1993, p. 2,).Last July, Regeneron Pharmaceuticals Inc. and Amgen Inc.jointly applied for FDA permission to test a different NGF,brain-derived neurotrophic factor (BDNF), to treatamyotrophic lateral sclerosis (ALS, or Lou Gehrig disease) inhumans (see BioWorld, July 20, 1993, p. 1).Now, scientists at Bristol-Myers Squibb (BMS) report in thecurrent issue of Nature (March 17), what happens totransgenic, knock-out mice born without the genes for twoNGF receptors. These cell-surface molecules convey the NGFmessages to their target neuronal cells, thus actually mediatingthe neurotrophins' biological activity.In two back-to-back Nature papers, Mariano Barbacid, BMS'svice president for molecular oncology, describes the behaviorof mice in whose embryonic stem cells he and his co-authorshad deleted the gene for one or another of these crucialreceptors.Deprived of Trk/NGF receptor gene function, one cohort oftransgenic mice at 10 days of life "failed to react to deeppinpricks in their whisker pads and rear paws, indicatingdefects in their trigeminal and peripheral sensory nervoussystems."The first paper's first author, neuroanatomist Richard Smeyne,told BioWorld that the Trk-defective mice showeddeficiencies in the central nervous system's basal forebrain,among other sites. "This region is implicated in Alzheimer'sdisease," he said. So those mice "should provide a useful toolto study the neuroprotective effects of neurotrophins, orcompounds with neurotrophic activity, in the basal forebrain."Animals bereft of a different receptor gene, neurotrophin-3trkC, "when placed on a rotating dowel...cannot maintain anupright posture and immediately tumble off," among otherdisabilities."These mice," Smeyne said, "display a bizarre movementdisorder remarkably similar to that observed in patients withdefective proprioception." This sensory activity, he explained,"allows us to know where our arms and legs are in space."Neurobiologist William Snider of Washington University inSt. Louis, a co-author of the second paper, worked out thisproprioception connection.Meanwhile, biologist Rudolf Jaenisch and his colleagues atthe Whitehead Institute for Biomedical Research, reported inNature a week earlier (March 10) that they have created astrain of mouse unable to produce its own brain-derivedneurotrophic factor (BDNF). "They showed defectivecoordination of movements and balance, with head bobbingand tilting and spinning. . ." Jaenisch told BioWorld: "Theseneurotrophins, as our paper shows us, affect very specificpopulations of cells. Those mice can't keep their balancebecause their inner-ear innervation is completely missing.They can hear, but can't keep their balance."Jaenisch calls the discovery of the neurotrophic factors, whichnow number four, "a very important breakthrough inneurobiology, [as] they are thought to be survival factors."He points to the impending Amgen/Regeneron clinical trial ofBDNF in ALS, a motor neuron disease, and surmises that theymay be important as well for treating neurodegenerativediseases in humans, such as Parkinson's or Alzheimer's.In his ongoing research, Jaenisch is asking the question, "Doour transgenic mice, when injured, regenerate as well as wild-type mice? We don't know the answer yet."Summing up, Barbacid told BioWorld, "the neuronal defectswe have observed in each of the strains of mice defective inTrk neurotrophin receptors provide unequivocaldemonstration that neurotrophins play a fundamental role inthe generation and maintenance of our nervous system."He added, "The ability to activate neurotrophin receptors withsmall, simple drugs may provide us with an importantpharmacological tool with which to fight neurodegenerativediseases in the future."

-- David N. Leff Science Editor

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