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Regulation of ocular size and shape during development
XV
5’YiV.S- October 1’980
more complex interactions of forces than the interactions controlling ‘shape changes in individual cells. During formation’ of the optic stalk and vesicle, all of the cells in the primordium have similar arrangements of filament bundles in the apical cytoplasm3. Meeting report by S. Robert Hilfer When the optic vesicle begins to grow dorsally, a zone of cells at the optic stalk/optic During the last few years, much information has accumulated on the embryonic processes vesicle junction develops bundles of microfilaments that stretch from cell apex to that shape organs and the study of ocular morphogenesis has been particularly productive. cell base. These longitudinal filament New contributions to knowledge on organogenesis of the eye was the subject of the Fifth bundles may play a role in changing the Symposium on Ocular.and Visual development, held in Philadelphia, PA, U.S.A. on 9 and direction of outgrowth. During invagina10 June 1980. tion the apices of cells at the margin of the tiation has occurred. The source of these retinal disc constrict but the apices of cells The role of cell birth and death cells finally has been established*. A toward the center lose the oriented bundles The developmental roles of increases in population of stem cells remains after the of filaments and increase in surface area. cell number as a result.of mitosis and of cell differentiating cells become postmitotic. The use of an in vitrd model system has loss through programmed death have been These stem cells divide to form new photoshown that invagination is dependent upon well documented. It has been suggested receptors and lead to a change in the rod/ an external source of calcium and prethat the patches of dying cells in the optic cone ratio in the mature retina. The initial vented by drugs that bind calmodulin and vesicle and stalk play a role in formation of formation of the lens is also dependent drugs that inhibit glycoconjugate synthesis. the optic cup and choroid fissure. Recent upon cell division. Once the lens primorLater growth of the lens also involves plots of the progression of cell death across dium is established, it undergoes little changes in cell shape. As the cells at the the primordium show that cell loss is increase in size until invagination is commargin of the lens undergo mitosis, they accompanied by formation of spaces betpleted. However, even though the size elongate and increase in volume. By using ween the future ganglion cells near the surface of the neural retina’. These spaces remains constant, the number of cells the drug, nocodazole, Beebe’ showed’that connect to form channels that stretch from increases and the cells become taller”. In elongation results from the increase in volan aphakic mutant of mice, formation of an ume and does not require the presence of the retina into the optic stalk. The ganglion abnormally small lens results from intact microtubules. detachment of cells from the primordium The morphogenetic events during eye The basic sequence of events involved and their movement into the cavity of the development are accompanied by changes in ocular development optic cup. Thus, the formation of a normal in cell surface molecules. These changes The optic primordium forms as an outlens depends upon a contiguous sheet of have been identified in.a number of ways7. growth of the forebrain when the original diverticulum becomes shaped into an lens cells and the force that results in Layering of the neural retina coincides with optic vesicle and optic stalk. The optic invagination may be contributed by changes in the density of intramembrane vesicle then invaginates to form the optic population pressure exerted in a restricted particles, in the behavior of isolated cells cup while the overlying ectoderm invagiarea. on a Percoll gradient, and in the aggregatnates to form tlie ocular lens. The inner ion characteristics of cell populations isohalf of the lens vesicle ,forrns fiber cells Shape and chemistry and growth continues by addition of new lated with Percoll. These characteristics fiber cells at the margin, where the lens is. It is generally accepted that shape suggest that distinct cell populations held in place by the optic cup. Subchanges in cell sheets are a result of cell appear in the retina during its specializasequently, the inner layer of the optic constriction caused by contractile filaments tion. A low molecular weight protein that cup becomes multilayered and develops and cell elongation caused by microtubule interferes with’cell aggregation (ligatin) has into the neural retina while the outer layer becomes the retinal pigmented sliding. Burnside has developed a model been isolated from retina and other tisepithelium. Specialization of the neural system to test these two morphogenetic sue,?. Ligatin acts as a baseplate in the retinal’ layer results in formation of shape changes using the retinal cells of the plasmalemma to bind glycoproteins and photoreceptors, intermediate cell layers, fish eye. In certain species, the rod cells glycolipids. Ligatin on an a$finity column and a ganglion cell layer that sends its elongate in the light and.shorten in the dark will bind proteins that are solubilized from axons along the optic stalk to the brain. ‘while cone cells display\ the reverse retina along with ligatin; the bound procell axons subsequently grow within these behavior. teins are released by phosphorylated manchannels. In the mutant mouse, orJ, cell Contraction of the cells is consistent with nose. This is’consistent with the presence of death does not occur in the optic primoran actin-myosin interaction, based upon mannose 6-phosphate in the ligatinchum. Although a normal optic cup forms, the arrangement of thick and thin filaments associated proteins. A dorsal-posterior to the ,,ganglion, cell axons remain disorgan- in the contracted and expanded states. In ventral-anterior gradient of a cell surface ized within the optic cup. Thus, cell death the ‘demembranized’ model, contraction antigen has been detected with a monoin the retina appears to direct the out- requires ATP and calcium. ions. The clonal antibody against neural cells. of the growth of the nerve fibers toward the brain. number of microtubules does not change dorsal-posterior retina91 This gradient Postnatal growth of the retina occurs during elongation, but the degree of over-
Regulation of ocular size ,and shape during development
@I ElsevierMonh-Hqlland:BiomediEal,Prea
!,$I80
TINS -October
XVI
the retina and forebrain derivatives. A differential distribution of surface macromolecules also exists in the lens. Fiber cells interdigitate in a highly ordered fashion and contain many more low resistance gap junctions than either marginal ceIb or lens epithelial cells’. The main component of the gap junction is a 26,000 dalton proteolipid that is highly tissue- and speciesspecific. Thus, the ordering of surface molecules in the retina and lens may contribute to their specific arrangements during organogenesis.
From the above, it seems clear that development of the eye does not occur by a single mechanism. Rather, formation of such a complex structure consisting of many tissue types must result from a sequence of carefully integrated processes.
3 Hilfer. 5 Maisel, Bradley,
1 Beebe, D. C., Johnson, M. C., Feagans, D. E. and Compart, P. J. in Ocular Size and Shape: Reguladon During Development (Hilfer, S. R. and Sheffield, J. B., eds), Springer-Verlag, New York (in press) 2 Bumside. B. in Ref. 1
Changing views on muscle’ receptors Meeting report by Arthur Prochazka and Anthony Taylor Owing to recent technical advances, rapid progress is being made in understanding the structural organization of mammalian muscle receptors, and their role in voluntary movement. The meeting at St Thomas’ Hospital Medical School on g-9 July 1980, brought together 105 leading motor control researchers. Formally presented critiques of the precirculated papers kept participants on their toes, and, it was generally agreed, greatly facilitated a genuine appraisal of the present state of knowledge in the field.
It is not widely appreciated that in a spindles activated during CNS stimulation. typical mammalian muscle nerve, alpha Interestingly, nuclear chain fibres were less motor fibres are outnumbered nearly two likely to be spontaneously active than static to one by fibres innervating muscle spindle bag2 fibres in Iight anaesthesia, suggesting a and tendon organ receptors. This heavy subdivision of CNS control of the static investment by the CNS in neural feedback fusimotor neurons innervating these fibres. and Y. Laporte has long fascinated physiologists, and yet F. Emonet-Denand the answer to the fundamental question showed that the action on spindle primaries ‘What do these afferents signal during vol- of dynamic fusimotor neurons firing at low untary movement?‘, has proved remarkrates only became -significant when the ably elusive. First, it is only in the last muscle was stretched. Details of the decade that tendon organs have clearly enhancement by static fusimotor action of been shown to signal active muscle force spindle secondary sensitivity to large down to very low levels. Second, the sen- length changes were provided by L. Jami. sitivity and bias of muscle spindles can be J. C. Houk attacked the use of linear transgreatly altered by the CNS through the fer functions to model the transducing spindles’ private motor fibres, the characteristics of spindle primaries, and fusimotor (y) efferents. Just how the CNS proposed instead a power function, involvuses fusimotor neurons was therefore a key ing multiplicative length and velocity issue at the meeting. terms. P. B. C. Matthews asked of this, ‘How much is new, how much is true and Receptor structure and sensitivity how much is general?’ His answers are to To set the scene, four research groups be found in the symposium book (see headed by D. Barker, I. A. Boyd, below). Y. Laporte, J. C. Houk and P. B. C. Matthews, discussed muscle spindle struc- Control of fusimotor neurons ture and sensitivity in cats. The controversy B. Appelberg and M. Hulliger then over whether static fusimotor neurons reviewed work on the selective central coninnervate a significant proportion of trol of dynamic fusimotor neurons, and dynamic bag1 intrafusal muscle fibres was their reflex activation. W. Z. Rymer settled in the negative. M. H. Gladden reported on dissociation of fusimotor and showed remarkable video films of living skeletomotor activity in decerebrate cats, @ Elsevicr/Norlh-Holiand Biomedical Press I980 /
R. and Yang, J.-j.
in Ref. 1
2001. (in press)
H., Alcala, J.. Kuszak, J.. Ireland. R. and Katar. M. in Ref. 1
Marchase,
R. B. and Jakoi,
E. R. in Ref. 1
Sheffield,
J. B. and Lynch,
M. in Ref. 1
Silver,
Reading lit
S. R., Brady,
4 Johns, P.Am.
M.,
J. in Ref. 1
Trisler, G. D.. Schneider, M. in Ref. 1 10 Zwaan,
1980
M. D. and Nirenberg,
J. in Ref. 1
S. R. Hiifer is at the Department of Biology, University, Philadelphia, PA 19122, U.S.A.
Temple
and A. Taylor and K. Appenteng proposed from their recordings in anaesthetized and normal animals, that a possible CNS control strategy was to set dynamic fusimotor drive to a constant level, but to vary static fusimotor drive as a ‘temporal template’ of the intended movement. Common to these papers was the feeling that y motoneurons were not rigidly co-activated with (Y motoneurons. P. H. Ellaway reviewed his group’s work on muscle afferent reflex action on y motoneurons, and D. R. Westbury described the electrical properties of y motoneurons. Afferent recordings during voluntary movement
G. E. Loeb and J. A. Hoffer proposed that in cat locomotion, dynamic fusimotor and skeletomotor neurons were coactivated in extensor-task muscles, while in flexor-task muscles, static fusimotor and skeletomotor neurons were co-activated. A. Prochazka and P. Wand preferred a more independent role for fusimotor neurons, and stressed the length-signalling function of spindles. The sensitivities of spindles were shown to vary for different classes of voluntary movement, largely independendy of muscle contraction. K. E. Hagbarth and A. B. Vallbo pointed out in their critiques that in movements involving active muscle shortening, deductions about fusimotor action from spindle discharge were fraught with difficulty. They were not satisfied that the data showed the independence claimed. These workers then reviewed the human spindle data and concluded that there was little or no evidence for fusimotor activation in the absence of skeletomotor activation. In the critique which followed, A. Taylor raised the important issue of afferent identification. Tendon organ afferents can all too easily be confused with spindle afferents, and tests such as muscle tapping and electrically evoked twitches may be insufficient for a
5’YiV.S- October 1’980
more complex interactions of forces than the interactions controlling ‘shape changes in individual cells. During formation’ of the optic stalk and vesicle, all of the cells in the primordium have similar arrangements of filament bundles in the apical cytoplasm3. Meeting report by S. Robert Hilfer When the optic vesicle begins to grow dorsally, a zone of cells at the optic stalk/optic During the last few years, much information has accumulated on the embryonic processes vesicle junction develops bundles of microfilaments that stretch from cell apex to that shape organs and the study of ocular morphogenesis has been particularly productive. cell base. These longitudinal filament New contributions to knowledge on organogenesis of the eye was the subject of the Fifth bundles may play a role in changing the Symposium on Ocular.and Visual development, held in Philadelphia, PA, U.S.A. on 9 and direction of outgrowth. During invagina10 June 1980. tion the apices of cells at the margin of the tiation has occurred. The source of these retinal disc constrict but the apices of cells The role of cell birth and death cells finally has been established*. A toward the center lose the oriented bundles The developmental roles of increases in population of stem cells remains after the of filaments and increase in surface area. cell number as a result.of mitosis and of cell differentiating cells become postmitotic. The use of an in vitrd model system has loss through programmed death have been These stem cells divide to form new photoshown that invagination is dependent upon well documented. It has been suggested receptors and lead to a change in the rod/ an external source of calcium and prethat the patches of dying cells in the optic cone ratio in the mature retina. The initial vented by drugs that bind calmodulin and vesicle and stalk play a role in formation of formation of the lens is also dependent drugs that inhibit glycoconjugate synthesis. the optic cup and choroid fissure. Recent upon cell division. Once the lens primorLater growth of the lens also involves plots of the progression of cell death across dium is established, it undergoes little changes in cell shape. As the cells at the the primordium show that cell loss is increase in size until invagination is commargin of the lens undergo mitosis, they accompanied by formation of spaces betpleted. However, even though the size elongate and increase in volume. By using ween the future ganglion cells near the surface of the neural retina’. These spaces remains constant, the number of cells the drug, nocodazole, Beebe’ showed’that connect to form channels that stretch from increases and the cells become taller”. In elongation results from the increase in volan aphakic mutant of mice, formation of an ume and does not require the presence of the retina into the optic stalk. The ganglion abnormally small lens results from intact microtubules. detachment of cells from the primordium The morphogenetic events during eye The basic sequence of events involved and their movement into the cavity of the development are accompanied by changes in ocular development optic cup. Thus, the formation of a normal in cell surface molecules. These changes The optic primordium forms as an outlens depends upon a contiguous sheet of have been identified in.a number of ways7. growth of the forebrain when the original diverticulum becomes shaped into an lens cells and the force that results in Layering of the neural retina coincides with optic vesicle and optic stalk. The optic invagination may be contributed by changes in the density of intramembrane vesicle then invaginates to form the optic population pressure exerted in a restricted particles, in the behavior of isolated cells cup while the overlying ectoderm invagiarea. on a Percoll gradient, and in the aggregatnates to form tlie ocular lens. The inner ion characteristics of cell populations isohalf of the lens vesicle ,forrns fiber cells Shape and chemistry and growth continues by addition of new lated with Percoll. These characteristics fiber cells at the margin, where the lens is. It is generally accepted that shape suggest that distinct cell populations held in place by the optic cup. Subchanges in cell sheets are a result of cell appear in the retina during its specializasequently, the inner layer of the optic constriction caused by contractile filaments tion. A low molecular weight protein that cup becomes multilayered and develops and cell elongation caused by microtubule interferes with’cell aggregation (ligatin) has into the neural retina while the outer layer becomes the retinal pigmented sliding. Burnside has developed a model been isolated from retina and other tisepithelium. Specialization of the neural system to test these two morphogenetic sue,?. Ligatin acts as a baseplate in the retinal’ layer results in formation of shape changes using the retinal cells of the plasmalemma to bind glycoproteins and photoreceptors, intermediate cell layers, fish eye. In certain species, the rod cells glycolipids. Ligatin on an a$finity column and a ganglion cell layer that sends its elongate in the light and.shorten in the dark will bind proteins that are solubilized from axons along the optic stalk to the brain. ‘while cone cells display\ the reverse retina along with ligatin; the bound procell axons subsequently grow within these behavior. teins are released by phosphorylated manchannels. In the mutant mouse, orJ, cell Contraction of the cells is consistent with nose. This is’consistent with the presence of death does not occur in the optic primoran actin-myosin interaction, based upon mannose 6-phosphate in the ligatinchum. Although a normal optic cup forms, the arrangement of thick and thin filaments associated proteins. A dorsal-posterior to the ,,ganglion, cell axons remain disorgan- in the contracted and expanded states. In ventral-anterior gradient of a cell surface ized within the optic cup. Thus, cell death the ‘demembranized’ model, contraction antigen has been detected with a monoin the retina appears to direct the out- requires ATP and calcium. ions. The clonal antibody against neural cells. of the growth of the nerve fibers toward the brain. number of microtubules does not change dorsal-posterior retina91 This gradient Postnatal growth of the retina occurs during elongation, but the degree of over-
Regulation of ocular size ,and shape during development
@I ElsevierMonh-Hqlland:BiomediEal,Prea
!,$I80
TINS -October
XVI
the retina and forebrain derivatives. A differential distribution of surface macromolecules also exists in the lens. Fiber cells interdigitate in a highly ordered fashion and contain many more low resistance gap junctions than either marginal ceIb or lens epithelial cells’. The main component of the gap junction is a 26,000 dalton proteolipid that is highly tissue- and speciesspecific. Thus, the ordering of surface molecules in the retina and lens may contribute to their specific arrangements during organogenesis.
From the above, it seems clear that development of the eye does not occur by a single mechanism. Rather, formation of such a complex structure consisting of many tissue types must result from a sequence of carefully integrated processes.
3 Hilfer. 5 Maisel, Bradley,
1 Beebe, D. C., Johnson, M. C., Feagans, D. E. and Compart, P. J. in Ocular Size and Shape: Reguladon During Development (Hilfer, S. R. and Sheffield, J. B., eds), Springer-Verlag, New York (in press) 2 Bumside. B. in Ref. 1
Changing views on muscle’ receptors Meeting report by Arthur Prochazka and Anthony Taylor Owing to recent technical advances, rapid progress is being made in understanding the structural organization of mammalian muscle receptors, and their role in voluntary movement. The meeting at St Thomas’ Hospital Medical School on g-9 July 1980, brought together 105 leading motor control researchers. Formally presented critiques of the precirculated papers kept participants on their toes, and, it was generally agreed, greatly facilitated a genuine appraisal of the present state of knowledge in the field.
It is not widely appreciated that in a spindles activated during CNS stimulation. typical mammalian muscle nerve, alpha Interestingly, nuclear chain fibres were less motor fibres are outnumbered nearly two likely to be spontaneously active than static to one by fibres innervating muscle spindle bag2 fibres in Iight anaesthesia, suggesting a and tendon organ receptors. This heavy subdivision of CNS control of the static investment by the CNS in neural feedback fusimotor neurons innervating these fibres. and Y. Laporte has long fascinated physiologists, and yet F. Emonet-Denand the answer to the fundamental question showed that the action on spindle primaries ‘What do these afferents signal during vol- of dynamic fusimotor neurons firing at low untary movement?‘, has proved remarkrates only became -significant when the ably elusive. First, it is only in the last muscle was stretched. Details of the decade that tendon organs have clearly enhancement by static fusimotor action of been shown to signal active muscle force spindle secondary sensitivity to large down to very low levels. Second, the sen- length changes were provided by L. Jami. sitivity and bias of muscle spindles can be J. C. Houk attacked the use of linear transgreatly altered by the CNS through the fer functions to model the transducing spindles’ private motor fibres, the characteristics of spindle primaries, and fusimotor (y) efferents. Just how the CNS proposed instead a power function, involvuses fusimotor neurons was therefore a key ing multiplicative length and velocity issue at the meeting. terms. P. B. C. Matthews asked of this, ‘How much is new, how much is true and Receptor structure and sensitivity how much is general?’ His answers are to To set the scene, four research groups be found in the symposium book (see headed by D. Barker, I. A. Boyd, below). Y. Laporte, J. C. Houk and P. B. C. Matthews, discussed muscle spindle struc- Control of fusimotor neurons ture and sensitivity in cats. The controversy B. Appelberg and M. Hulliger then over whether static fusimotor neurons reviewed work on the selective central coninnervate a significant proportion of trol of dynamic fusimotor neurons, and dynamic bag1 intrafusal muscle fibres was their reflex activation. W. Z. Rymer settled in the negative. M. H. Gladden reported on dissociation of fusimotor and showed remarkable video films of living skeletomotor activity in decerebrate cats, @ Elsevicr/Norlh-Holiand Biomedical Press I980 /
R. and Yang, J.-j.
in Ref. 1
2001. (in press)
H., Alcala, J.. Kuszak, J.. Ireland. R. and Katar. M. in Ref. 1
Marchase,
R. B. and Jakoi,
E. R. in Ref. 1
Sheffield,
J. B. and Lynch,
M. in Ref. 1
Silver,
Reading lit
S. R., Brady,
4 Johns, P.Am.
M.,
J. in Ref. 1
Trisler, G. D.. Schneider, M. in Ref. 1 10 Zwaan,
1980
M. D. and Nirenberg,
J. in Ref. 1
S. R. Hiifer is at the Department of Biology, University, Philadelphia, PA 19122, U.S.A.
Temple
and A. Taylor and K. Appenteng proposed from their recordings in anaesthetized and normal animals, that a possible CNS control strategy was to set dynamic fusimotor drive to a constant level, but to vary static fusimotor drive as a ‘temporal template’ of the intended movement. Common to these papers was the feeling that y motoneurons were not rigidly co-activated with (Y motoneurons. P. H. Ellaway reviewed his group’s work on muscle afferent reflex action on y motoneurons, and D. R. Westbury described the electrical properties of y motoneurons. Afferent recordings during voluntary movement
G. E. Loeb and J. A. Hoffer proposed that in cat locomotion, dynamic fusimotor and skeletomotor neurons were coactivated in extensor-task muscles, while in flexor-task muscles, static fusimotor and skeletomotor neurons were co-activated. A. Prochazka and P. Wand preferred a more independent role for fusimotor neurons, and stressed the length-signalling function of spindles. The sensitivities of spindles were shown to vary for different classes of voluntary movement, largely independendy of muscle contraction. K. E. Hagbarth and A. B. Vallbo pointed out in their critiques that in movements involving active muscle shortening, deductions about fusimotor action from spindle discharge were fraught with difficulty. They were not satisfied that the data showed the independence claimed. These workers then reviewed the human spindle data and concluded that there was little or no evidence for fusimotor activation in the absence of skeletomotor activation. In the critique which followed, A. Taylor raised the important issue of afferent identification. Tendon organ afferents can all too easily be confused with spindle afferents, and tests such as muscle tapping and electrically evoked twitches may be insufficient for a