Brain‐derived proteins that rescue spinal motoneurons from cell death in the chick embryo: Comparisons with target‐derived and recombinant factors

Abstract

Spinal motoneurons that normally die during early development can be rescued by a variety of purified growth or neurotrophic factors and target tissue extracts. There is also indirect evidence that brain or supraspinal afferent input may influence lumbar motoneuron survival during development and that this effect may be mediated by central nervous system-derived trophic agents. This report examines the biological and biochemical properties of motoneuron survival activity obtained from extracts of the embryonic chick brain. Treatment with an ammonium sulfate (25% to 75%) fraction of embryonic day 16 (E16) or E10 brain extracts rescued many spinal motoneurons that otherwise die during the normal period of cell death in vivo (E6 to E10). The same fractions also enhanced lumbar motoneuron survival following deafferentation. There were both similarities and differences between the active fractions derived from brain extracts (BEX) when compared with extracts derived from target muscles (MEX) or with purified neurotrophic factors. Survival activity from E10 BEX was as effective in promoting motoneuron survival as E10 MEX and more effective than astrocyte-conditioned media. Unlike MEX, the active fractions from BEX also rescued placode-derived nodose ganglion cells. In addition, unlike nerve growth factor and brain-derived neurotrophic factor, active BEX fractions did not rescue neural crest-derived dorsal root ganglion cells or sympathetic ganglion neurons. Interestingly, among many cranial motor and other brainstem nuclei examined, only the survival of motoneurons from the abducens nucleus was enhanced by BEX. Active proteins obtained from BEX were further separated by gel filtration chromatography and by preparative isoelectric focusing techniques. Activity was recovered in a basic (pI 8) and an acidic (pI 5) small molecular weight protein fraction (20 kD or less). The specific activity of the basic fraction was increased x66 when compared with the specific activity of crude BEX, and the basic fraction had a slightly higher specific activity than the acidic fraction. The biological and biochemical properties of these fractions are discussed in the context of known neurotrophic factors and their effects on normal and lesion-induced motoneuron death during development.

Focal expression of glial cell line-derived neurotrophic factor in developing mouse limb bud

“…The developmental functions of most of these growth factors have not been revealed in null mutant mice and therefore remain unclear. Evidence that growth factors act cooperatively or synergistically is provided by work on motoneurons in culture (see Johnson et al 1995 and references therein) but demonstrating that there are functional synergistic effects in vivo has been difficult (see Oppenheim et al 1993). One attractive hypothesis is that different factors may act to support survival at different stages of development.…”

Distinct muscle targets do not vary in the developmental regulation of brain‐derived neurotrophic factor

“…The motoneuron survival-promoting effects of musclederived neurotrophic factors, including BDNF, are well documented both in vitro and in vivo (Dohrmann et al, 1987;Bloch-Gallego et al, 1991;Oppenheim et al, 1992Oppenheim et al, , 1993Johnson et al, 1995). BDNF, a member of the neurotrophin family (Lewin and Barde, 1996), is a musclederived trophic factor for motoneurons, and exogenous BDNF is capable of rescuing motoneurons from both naturally occurring and injury-induced cell death (Oppenheim et al, 1992;Sendtner et al, 1992;Koliatsos et al, 1993;McKay et al, 1996).…”

Neurotrophic factor regulation of developing avian oculomotor neurons: Differential effects of BDNF and GDNF

“…Sensory ganglia express brain-derived neurotrophic factor (BDNF) mRNA (Ernfors et al, 1990;Schecterson and Bothwell, 1992) and transport BDNF anterogradely to the central nervous system (CNS) (Zhou and Rush, 1996;Michael et al, 1997), and may release it as a trophic agent for motoneurons (Schecterson and Bothwell, 1992;Yan et al, 1993;Zhou and Rush, 1996). Consistent with the notion that BDNF may act as an afferent-derived trophic factor, deafferentation-induced cell death of spinal motoneurons can be prevented by exogenous BDNF (Oppenheim et al, 1992;Yin et al, 1994;Johnson et al, 1995). BDNF is also expressed in developing muscle, the target of motoneurons (Hallböök et al, 1993;Henderson et al, 1993;Kwon and Gurney, 1996), and exogenous BDNF is retrogradely transported from the target to spinal and cranial motoneurons after the period of developmental cell death and during the late phase of normal developmental cell death (Yan et al, 1993;McKay et al, 1996).…”

“…Trophic factors with effects on motor neurons may be derived from the target, from the pathway (glial cells), or from the CNS (Yan et al, 1993;Johnson et al, 1995;Oppenheim, 1996). BDNF may act as a physiological survival factor for spinal motoneurons that is derived from the sensory ganglia via their synaptic input to this cell type.…”