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The guidance of growing axons
2;9
Brain malformations in fetal mice resulting the gastrulation stage of embryogenesis
from acute maternal alcohol exposure during
Sulik I, K.K., and Lauder 2, J.M. Departments of Anatomyl, 2 and Ophthalmology I, University of North Carolina, Chapel Hill, N.C. 27514 Deficiencies of the antero-medial aspect of the embryonic dis~result from acute maternal alcohol administration to C57BI/6J mice by either the i.p. or gastric intubation route on gestational day 7. Subsequent defects of the brain and face are consistent with those observed in severe human fetal alcohol syndrome (FAS). Light and scanning electron microscopic (SEM) analyses of brain morphogenesis illustrate a wide s p e ~ trum of defects which primarily involve the ventro-medial forebrain. At the mild end of the spectrum minor deficiencies are observed in the developing septal nuclei, whereas in the most severely affected animals many defects in anterior brain development are found which are consistent with those commonly recognized as belonging to the holoprosencephaly series. Among these defects are fusion of paired medial structures, (e.g., the septal nuclei), enlarged lateral ventricles, narrowing of the third ventricle, thinning of the cerebral cortex, and absence of the corpus callosum. Acute alcohol exposure may interfere with gastrulation and secondarily affect neural plate induction via a deficiency in prechordal mesoderm. The insult to the neural plate may be direct, or teratogenesis may involve indirect mechanisms. These studies demonstrate that a "critical period" for alcohol neuro-teratogenesis exists which corresponds to the third week of human gestation. Supported by DISCUS Grant 1722-017 and NIH grant NS 15706.
ROUNDTABLE
8
The Guidance of Growing Axons Dr. Robert Levine,
Biology Department,
}IcGill University
The factors which guide growing axons during development and regeneration have been the subject of systematic studies since the end of the last century. These studies have spanned a broad range of species and have involved numerous forces, both intrinsic and extrinsic to the neuron, to explain the results of axon growth. At present, it seems clear that the eventual path that growing axon takes must be the resultant of the sum of the forces which are acting on it and which are exerted by it at any given time. These forces include those which arise from adhesive interactions mediated by molecules bound to cell membranes and/or the extracellular matrix, from changes in the pattern of axonal growth mediated by molecules in solution in the extracellular space, and from the disposition of physical barriers in the terrain through which the axon must grow. In addition, factors which direct axonal growth may also be considered from a cellular point of view, in terms of which cells are producing relevant molecules or forming pathways for the growing axons to follow. Our round table will attempt to examine the problem of axonal guidance from a diverse set of vantage points. We will contrast various experimental systems and interpretations in order to evince corm~on principles which may underlie axonal growth in a wide variety of circumstances.
" P a t h f i n d i n g by p i o n e e r n e u r o n s " ; C a u d y , M . & Bentley, and Z o o l o g y Dept., Univ. of C a l i f o r n i a , Berkeley.
D.R.;
Biophysics
Group
I d e n t i f i e d p i o n e e r axons form a c o n t i n u o u s s u b s t r a t e p a t h w a y for g u i d i n g later g r o w i n g s e n s o r y and m o t o r a x o n s in the g r a s s h o p p e r e m b r y o n i c limb, and thereby establish the t o p o l o g y of o n e of the c h a r a c t e r i s t i c major nerve b r a n c h e s s e e n in the a d u l t . E v i d e n c e from both normal and experimentally manipulated limbs suggests that the pioneer g r o w t h c o n e s a r e g u i d e d by growing along a chain of n o n a d j a c e n t guidepost cells (G.P.'s), whose p l a c e m e n t d e t e r m i n e s th e p a t h w a y . T h e s e c e l l s are also i d e n t i f i e d neurons, but have n o t y e t b e g u n a x o n o g e n e s i s . E a c h of t h e s e G.P. n e u r o n s can also p i o n e e r the p a t h w a y if the n o r m a l pioneer a x o n is a b s e n t , and the p i o n e e r neuron a l s o s e r v e s as a G.P. for l a t e r , more distal, pioneering growth cones. Furthermore, both G.P.'s and pioneers initially s e n d out l o n g , randomly directed filopodia from their somata, a n d t h e n f r o m their g r o w t h cones, w h i c h may guide the g r o w t h c o n e s by m a k i n g direct contact with either n o n a d j a c e n t G.P.'s or a c o n t i n u o u s pioneer a x o n . Thus, time of a x o n o g e n e s i s m a y be the only d i f f e r e n c e between G.P. and p i o n e e r neurons, and both may use direct f i p o p o d i a l contact with specific substrate m e m b r a n e for g r o w t h cone g u i d a n c e .
Brain malformations in fetal mice resulting the gastrulation stage of embryogenesis
from acute maternal alcohol exposure during
Sulik I, K.K., and Lauder 2, J.M. Departments of Anatomyl, 2 and Ophthalmology I, University of North Carolina, Chapel Hill, N.C. 27514 Deficiencies of the antero-medial aspect of the embryonic dis~result from acute maternal alcohol administration to C57BI/6J mice by either the i.p. or gastric intubation route on gestational day 7. Subsequent defects of the brain and face are consistent with those observed in severe human fetal alcohol syndrome (FAS). Light and scanning electron microscopic (SEM) analyses of brain morphogenesis illustrate a wide s p e ~ trum of defects which primarily involve the ventro-medial forebrain. At the mild end of the spectrum minor deficiencies are observed in the developing septal nuclei, whereas in the most severely affected animals many defects in anterior brain development are found which are consistent with those commonly recognized as belonging to the holoprosencephaly series. Among these defects are fusion of paired medial structures, (e.g., the septal nuclei), enlarged lateral ventricles, narrowing of the third ventricle, thinning of the cerebral cortex, and absence of the corpus callosum. Acute alcohol exposure may interfere with gastrulation and secondarily affect neural plate induction via a deficiency in prechordal mesoderm. The insult to the neural plate may be direct, or teratogenesis may involve indirect mechanisms. These studies demonstrate that a "critical period" for alcohol neuro-teratogenesis exists which corresponds to the third week of human gestation. Supported by DISCUS Grant 1722-017 and NIH grant NS 15706.
ROUNDTABLE
8
The Guidance of Growing Axons Dr. Robert Levine,
Biology Department,
}IcGill University
The factors which guide growing axons during development and regeneration have been the subject of systematic studies since the end of the last century. These studies have spanned a broad range of species and have involved numerous forces, both intrinsic and extrinsic to the neuron, to explain the results of axon growth. At present, it seems clear that the eventual path that growing axon takes must be the resultant of the sum of the forces which are acting on it and which are exerted by it at any given time. These forces include those which arise from adhesive interactions mediated by molecules bound to cell membranes and/or the extracellular matrix, from changes in the pattern of axonal growth mediated by molecules in solution in the extracellular space, and from the disposition of physical barriers in the terrain through which the axon must grow. In addition, factors which direct axonal growth may also be considered from a cellular point of view, in terms of which cells are producing relevant molecules or forming pathways for the growing axons to follow. Our round table will attempt to examine the problem of axonal guidance from a diverse set of vantage points. We will contrast various experimental systems and interpretations in order to evince corm~on principles which may underlie axonal growth in a wide variety of circumstances.
" P a t h f i n d i n g by p i o n e e r n e u r o n s " ; C a u d y , M . & Bentley, and Z o o l o g y Dept., Univ. of C a l i f o r n i a , Berkeley.
D.R.;
Biophysics
Group
I d e n t i f i e d p i o n e e r axons form a c o n t i n u o u s s u b s t r a t e p a t h w a y for g u i d i n g later g r o w i n g s e n s o r y and m o t o r a x o n s in the g r a s s h o p p e r e m b r y o n i c limb, and thereby establish the t o p o l o g y of o n e of the c h a r a c t e r i s t i c major nerve b r a n c h e s s e e n in the a d u l t . E v i d e n c e from both normal and experimentally manipulated limbs suggests that the pioneer g r o w t h c o n e s a r e g u i d e d by growing along a chain of n o n a d j a c e n t guidepost cells (G.P.'s), whose p l a c e m e n t d e t e r m i n e s th e p a t h w a y . T h e s e c e l l s are also i d e n t i f i e d neurons, but have n o t y e t b e g u n a x o n o g e n e s i s . E a c h of t h e s e G.P. n e u r o n s can also p i o n e e r the p a t h w a y if the n o r m a l pioneer a x o n is a b s e n t , and the p i o n e e r neuron a l s o s e r v e s as a G.P. for l a t e r , more distal, pioneering growth cones. Furthermore, both G.P.'s and pioneers initially s e n d out l o n g , randomly directed filopodia from their somata, a n d t h e n f r o m their g r o w t h cones, w h i c h may guide the g r o w t h c o n e s by m a k i n g direct contact with either n o n a d j a c e n t G.P.'s or a c o n t i n u o u s pioneer a x o n . Thus, time of a x o n o g e n e s i s m a y be the only d i f f e r e n c e between G.P. and p i o n e e r neurons, and both may use direct f i p o p o d i a l contact with specific substrate m e m b r a n e for g r o w t h cone g u i d a n c e .