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© The Rockefeller University Press,
0021-9525/1998//1167 $5.00
The Journal of Cell Biology, Volume 140, Number 5,
, 1998 1167-1176
Article |
Antagonistic Roles of Neurofilament Subunits NF-H and NF-M Against NF-L in Shaping Dendritic Arborization in Spinal Motor Neurons
Dendrites play important roles in neuronal function. However, the cellular mechanism for the growth and maintenance of dendritic arborization is unclear. Neurofilaments (NFs), a major component of the neuronal cytoskeleton, are composed of three polypeptide subunits, NF-H, NF-M, and NF-L, and are abundant in large dendritic trees. By overexpressing each of the three NF subunits in transgenic mice, we altered subunit composition and found that increasing NF-H and/or NF-M inhibited dendritic arborization, whereas increasing NF-L alleviated this inhibition. Examination of cytoskeletal organization revealed that increasing NF-H and/or NF-M caused NF aggregation and dissociation of the NF network from the microtubule (MT) network. Increasing NF-H or NF-H together with NF-M further reduced NFs from dendrites. However, these changes were reversed by elevating the level of NF-L with either NF-H or NF-M. Thus, NF-L antagonizes NF-H and NF-M in organizing the NF network and maintaining a lower ratio of NF-H and NF-M to NF-L is critical for the growth of complex dendritic trees in motor neurons.
Abbreviations used in this paper: MAP, microtubule-associated protein; MT, microtubule; NF, neurofilaments.
Address correspondence to Zuoshang Xu, Worcester Foundation for Biomedical Research, 222 Maple Avenue, Shrewsbury, MA 01545. Tel.: (508) 842-8921, ext. 255. Fax: (508) 842-3915. E-mail: xu{at}sci.wfbr.edu
NEURONS are polarized cells that receive and integrate synaptic input on the surface of their dendrites and cell bodies, and conduct action potentials to distal targets via their axons. Ample evidence indicates that the neuronal cytoskeleton plays important roles in the development of neuronal polarity (Caceres and Kosik, 1990; Hirokawa, 1991; Caceres et al., 1992). Composed of three polypeptide subunits (NF-H, NF-M, and NF-L), neurofilaments (NFs)1 belong to the intermediate filament family (Shaw, 1991) and are the most abundant cytoskeletal element in large neurons with long myelinated axons (Xu et al., 1994). Recent experiments have convincingly established that NFs play an indispensable role in the development and maintenance of normal axonal caliber (reviewed in Lee and Cleveland, 1996), a critical determinant of axonal conduction velocity (Arbuthnott et al., 1980). However, whether NFs also play a role in shaping the dendritic structure has not been explored.
Dendrites play an important role in neuronal function, particularly in neuronal plasticity (Yuste and Tank, 1996; Sejnowski, 1997). Dendrites create most of the surface area for synapse formation (Ulfhake and Kellerth, 1981; Brännström, 1993; Chen and Wolpaw, 1994), influence the integration of synaptic inputs and neuronal excitation (Mainen and Sejnowski, 1996; Magee and Johnston, 1997; Markram et al., 1997), and allow neurons to compartmentally regulate the distribution of a variety of cellular components, including cytoskeletal components (Kanai and Hirokawa, 1995; Kosik and Finch, 1987), ion channels, and receptors (Crino and Eberwine, 1996; Johnston et al., 1996). The highly diverse patterns of dendritic arborization reflect the unique connections and functions of the different neuronal populations. During development, the shape of each individual neuron is determined by a complex interaction between its genetic program and the surrounding environment (Purves and Lichtman, 1985). Consistent with its role in neuronal plasticity, the structure of dendrites remains plastic in both developing and mature neurons and is subject to modulation by neuronal activity, various neurotrophic factors and the size of target tissue (Greenough, 1984; Purves et al., 1986; Voyvodic, 1989; McAllister et al., 1996).
Thus, dendritic architecture is influenced by a variety of extrinsic factors. However, the intrinsic mechanism for the development and maintenance of dendritic architecture is relatively unexplored. The abundance of NFs in dendrites in many types of neurons (Peters et al., 1991) suggests that they may play a role in the growth and maintenance of elaborate dendritic trees. To investigate this possibility, we altered the NF subunit composition by selectively overexpressing each of the three NF subunits in transgenic mice (Xu et al., 1996) and examined the dendritic architecture of spinal motor neurons. We found that an increased ratio of NF-H and/or NF-M to NF-L inhibited dendritic arborization, whereas a reduction in this ratio promoted it. Further examination of the cytoskeletal organization revealed that a high ratio of NF-H and NF-M to NF-L led to NF aggregation, dissociation of neurofilament and microtubule networks and depletion of NFs from dendrites. These results demonstrate that NF-H and NF-M play different roles from NF-L in organizing neuronal cytoskeleton and influencing dendritic growth. They also illustrate the importance of maintaining a lower ratio of NF-H and NF-M to NF-L during development, which favors the growth of neuronal processes.
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50 (line 42) and NF-H (line 35), have been produced and characterized in detail previously (Monteiro et al., 1990; Xu et al., 1993, 1996; Wong et al., 1995; Marszalek et al., 1996). All three lines express their transgene products at the highest level in spinal cord motor neurons. To produce mice overexpressing two NF subunits simultaneously, the three lines were intercrossed and transgenic mice carrying two transgenes: NF-L and NF-M, NF-L and NF-H, or NF-M and NF-H were determined by Southern blot as described previously (Xu et al., 1993, 1996; Wong et al., 1995; Marszalek et al., 1996). All mice used in this study were 17 d old.
Measurement of NF Protein Levels
Mice were killed at 17 d after birth and spinal cords were dissected and frozen immediately on dry ice. A piece of tail was saved from each mouse and used for transgene typing as described above. A quantitative Western blot described previously (Xu et. al., 1996) was used to quantify each NF subunits.
Tissue Preparation and Morphological Analysis
The rapid Golgi method was used as described in Morest (1981). Mice were fixed by transcardial perfusion using 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4). A 0.3-cm segment of the lumbar enlargement of the spinal cord, centered at the attachment site of L5 ventral roots, was dissected out, immersed in 3% potassium bichromate and 1% osmium tetroxide for 3 d, and then stained with silver nitrate for 48 h. 70-µm transverse sections from the stained tissue was cut using a vibratome (TPI Inc., St. Louis, MO) and examined under a light microscope. Spinal cords that contained more than seven clearly stained motor neurons were further analyzed.
Motor neurons located within the anterior horn, with their cell bodies intact and larger than 30 µm in diameter, and with all the neurites clearly traceable, were drawn using a Nikon drawing tube at 300x magnification. The drawings were scanned into a computer using a HP ScanJet 3c. An equal number of neurons were then randomly selected from all the neurons drawn from each animal and measured using MetaMorph software (Universal Imaging Co., West Chester, PA). The number of neurons measured are 33 from 3 wild-type mice, 32 from 4 H mice, 21 from 3 M mice, 33 from 3 L mice, 20 from 2 HM mice, 20 from 2 LH mice, and 22 from 2 LM mice. The following definitions were used when measuring dendrites. Dendritic segment: the length of a dendrite between two branch points, between the cell body and the first branch point (primary dendrite), or the terminal segment that no longer branches. Dendritic tree: a primary dendrite and all the branches derived from it. The number of dendritic trees in a neuron equals the number of primary dendrites. Segment ratio: the ratio between the number of dendritic segments in the nth + one order and that in the nth order per neuron.
In these measurements, axons were not excluded because it was not possible to differentiate the axon from the dendrites in every neuron with full confidence. However, the inclusion of axons in the measurements of neurons with numerous and long dendrites was not expected to influence the results significantly because each neuron contains only one axon and the length of the axon is limited by sectioning. For neurons with significantly shortened dendrites, the contribution of an axon could be significant, and therefore, the measured dendritic length in these neurons would bias towards an overestimation. This would tend to diminish the difference between the wild-type and transgenic neurons. Despite this tendency, statistically significant differences were found between the wild-type and several transgenic lines (see Results).
To measure dendritic diameter and tapering, five neurons randomly selected from the above motor neuron pool were further drawn using 1,000x magnification. The diameters at both ends of each dendritic segment and the length of the dendritic segments were measured from the drawings. The proximal end of the primary dendrite was determined using the following criteria: the transitions from cell body membrane to dendrite membrane were located at points at which the membrane changed from convex out to concave out. A smooth convex arc consistent with the rest of the soma outline was drawn between the points and the midpoint of the arc was defined as the origin of primary dendrite (see Chen and Wolpaw, 1994). The average diameter of a segment was calculated as the average of the proximal and distal diameters. Dendritic tapering was the difference between the initial diameter and the end diameter of a dendritic segment per 100 µm of segment length. Rall's ratio was calculated from (
[Ddaughter3/2])/ (Dparent3/2) using the average diameter of dendritic segments. All statistical comparisons were carried out using Wilcoxon two-sample rank sum test.
For EM, mouse tissues were initially fixed by transcardial perfusion with a solution of 0.1 M sodium phosphate (pH 7.4), 4% paraformaldehyde, 2.5% glutaraldehyde, followed by further fixation in the same fixative for 24 h at 4°C. Tissues were then dissected out, postfixed with 2% osmium tetroxide in 0.1 M phosphate buffer, dehydrated in a graded ethanol series, and embedded in Epon-Araldite resin. 1-µm sections were stained with toluidine blue and examined by light microscopy. Thin sections were stained with uranyl acetate and lead citrate, examined and photographed in an electron microscope (model EM301; Philips Electron Optics, Mahwah, NJ).
Immunohistochemistry and Confocal Microscopy
Animals were perfused as described above using 4% paraformaldehyde in 0.1 M phosphate buffer. Spinal cords were dissected out and cut into 20-µm transverse sections with a vibratome. Sections were stained overnight at 4°C using a monoclonal antibody against MAP2 (a gift from Dr. R. Vallee; De Camilli et al., 1984) and a rabbit polyclonal antibody against NF-L (Xu et al., 1993). Rhodamine-conjugated goat anti–rabbit IgG and fluorescein-conjugated goat anti–mouse IgG (Jackson ImmunoResearch Laboratories Inc., West Grove, PA) were used as secondary antibodies. The doubly stained sections were examined with a scanning laser confocal microscope (model 1024; Bio-Rad Laboratories, Hercules, CA).
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60 and 30%, respectively, whereas overexpression of NF-L (L mice) did not cause a significant change (Figs. 1 and 2). The shortening caused by overexpression of either NF-H or NF-M was partially or completely alleviated by a simultaneous increase in the level of NF-L (compare H mice with LH mice and M mice with LM mice in Figs. 1 and 2). A simultaneous increase of both NF-H and NF-M nearly eliminated dendrites (Figs. 1 and 2).
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To confirm this point, we examined the cytoskeletal organization in mice that overexpress two subunits simultaneously. Increasing NF-L together with either NF-M or NF-H prevented the formation of NF aggregates and the dissociation of NF and MT networks (Fig. 7, A–F). Most notably, it prevented the depletion of NFs from dendrites (Fig. 7, D–F, arrows) that was caused by increasing NF-H alone (Fig. 6, G–I, arrows). Thus, increasing NF-L reverses the alterations in cytoskeletal organization caused by increasing NF-H and NF-M despite a further increase in the total NF protein content (Table I). In contrast to the role of increasing NF-L, increasing both NF-M and NF-H caused the most severe aggregation of NFs (Fig. 7, G–I, arrowheads) and depletion of NFs from dendrites and dendritic attrition (Fig. 7, G–I, arrows). Thus, a high ratio of NF-H and NF-M to NF-L, rather than an increase in the total amount of NF polypeptides, leads to the alteration in cytoskeletal organization and dendritic arborization.
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To determine how changes in NF subunit composition affected NF distribution in dendrites, and in particular, to find out how neurofilament network was disrupted abruptly in the proximal dendrites, we further examined dendritic initiation zone using EM. In wild-type mice there were abundant neurofilaments in dendrites (Fig. 9, A and B). They formed parallel bundles and were a continuous extension of the NF network in the cell body (Fig. 9, A and B). In sharp contrast, the NFs forming aggregates in the cell body in H (Fig. 9, C and D) or HM mice (Fig. 9, G and H) failed to extend into the proximal dendrites, leaving mostly microtubules in the proximal dendrites. The disrupted extension of NFs into the proximal dendrites caused by an increase in NF-H was reversed by increasing NF-L (Fig. 9, I and J). In M (Fig. 9 E), L (Fig. 9 F), and LM (not shown) mice the number of NFs was increased in the proximal dendrites and the continuous extension of the NF network from the cell body to the proximal dendrites was not affected.
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Previous experiments have shown that a high ratio of NF-H and NF-M to NF-L inhibited radial axonal growth (Wong et al., 1995; Marszalek et al., 1996; Xu et al., 1996). Our current efforts demonstrate that the high ratio is also inhibitory to dendritic growth, thus proving that a high ratio of NF-H and NF-M to NF-L is generally inhibitory to neuronal process growth. Our observations suggest that this inhibition is derived from interference with the interaction between NF and MT networks by the increased ratio of NF-H and/or NF-M to NF-L that leads to a dissociation of the NF and MT networks (Figs. 6–8). Because long distance intracellular organelle transport is known to be microtubule dependent (Vallee and Bloom, 1991), such a dissociation could lead to an inhibition of NF transport, resulting in a decreased NF content in both axons and dendrites (Wong et al., 1995; Marszalek et al., 1996; Xu et al., 1996; Figs. 6, 7, 8) and an accumulation of NFs in cell bodies (Fig. 8).
A close association of intermediate filaments and MTs in cultured cells has been widely observed and disruption of this interaction leads to a collapse of intermediate filament network into aggregates (Blose et al., 1984; Gyoeva and Gelfand, 1991). We show that NFs are closely associated with MTs in neurons in vivo. The dissociation of NFs from MTs and the formation of NF aggregates after the increased ratio of NF-H and/or NF-M to NF-L suggest that NF-H and NF-M weaken the association of NFs with MTs and promote NF self association. The reversal of this dissociation and NF aggregation by an increase in NF-L suggests that NF-L plays an interactive role between NFs and MTs. Candidates for mediating this interaction include microtubule associated proteins, such as MAP2 and tau. Both have been shown to bind to microtubules as well as NF-L in vitro (Heimann et al., 1985; Miyata et al., 1986). Other potential mediators include microtubule-based motors (Gyoeva and Gelfand, 1991) and the intermediate filament-associated protein plectin (Svitkina et al., 1996).
The mechanism for the inhibition of the interaction between NFs and MTs by the high ratio of NF-H and/or NF-M to NF-L is not clear. One possibility is that an increased ratio of NF-H and/or NF-M to NF-L may increase the density of their COOH-terminal tails projecting from the filament core where NF-L resides (Hirokawa et al., 1984; Hirokawa, 1991). Because NF-L may play an interactive role with MTs, a high density of NF-H and NF-M tails could block this interaction due to stereo hindrance. Concomitant with inhibiting the interaction between NFs and MTs, NF-H and NF-M may also promote self-association among NFs (Xu et al., 1996), mediated by their COOH-terminal tails of these molecules (Hirokawa et al., 1984; Hirokawa, 1991). Thus, both interference with the interaction between NFs and MTs and a tendency for self-association may contribute to the formation of NF aggregates when the ratio of NF-H and/or NF-M to NF-L is increased. By the same token, increasing NF-L lowers the density of NF-H and NF-M tails, which in turn reduces the stereo hindrance, therefore allowing the interaction between NFs and MTs to occur.
The reduced NF content in dendrites as a consequence of an increased ratio of NF-H and NF-M to NF-L is consistent with a reduction in transport of NFs into neuronal processes and is a likely cause that leads to structural changes in dendrites. These changes include reductions in diameter of proximal dendrites (Fig. 5), the number of primary dendrites (Fig. 3 A), distal dendritic branching (Fig. 4) and the length of dendritic segments (Fig. 3 D). Although increasing NF-L alone does not affect most of these parameters, when increased together with NF-H or NF-M, it partially or completely alleviated the reduction in these dendritic parameters (Figs. 1–5). The most dramatic effects are in the recovery of proximal dendritic diameter and the number of primary dendrites in LH mice (Figs. 5 and 3 A). Coincident with these recoveries is the recovery of NF content in the proximal dendrites (Figs. 7, D–F and 9, I and J). Interestingly, recovery of the length of dendritic segments (Fig. 3, A and D) is not observed and the recovery of distal dendritic branching is incomplete in LH mice (Fig. 4), suggesting that the effect of increasing NF-L is limited to the proximal dendrites.
In a mathematical simplification of the electrical properties of complex dendritic arborization, Rall used a single element or equivalent cylinder to describe a dendritic tree (Rall, 1995). Rall's ratio is a constraint in this model that requires ([Ddaughter3/2])/(Dparent3/2) = 1 (D represents diameter of dendritic segments). Our results show a Rall's ratio being close to one in wild-type mice, agreeing with other studies (Ulfhake and Kellerth, 1981; Brännström, 1993; Chen and Wolpaw, 1994). Changes in NF subunit composition do not lead to a significant deviation from the Rall's ratio in the overall dendritic structure. Only the ratio between the second and the first order dendrites is reduced in all except L mice, whereas the ratios in distal dendrites are unaffected (Fig. 5).
These findings shed light on the developmental regulation of NF subunit expression. The expression of NF-L and NF-M closely follows neuronal differentiation (Carden et al., 1987; Kost et al., 1992) and is associated with the earliest stages of neuronal process growth (Cochard and Paulin, 1984; Landmesser and Swain, 1992; Crino and Eberwine, 1996). However, the expression of NF-H does not increase significantly until >10 d after birth (Shaw and Weber, 1982; Pachter and Liem, 1984). Whereas the coexpression of NF-L and NF-M during the early stages of development is consistent with the finding that at least two subunits, composed of NF-L and either NF-M or NF-H, are required for NF assembly in cells (Ching and Liem, 1993; Lee et al., 1993), maintaining a low level of NF-H may be important for dendritic growth. On this note, it is interesting to notice that at age 17 d, the ratio of NF-H to NF-L in wild-type mice is 0.06 (Table I), approximately threefold lower than the ratio in 6-wk-old mice (Xu et. al., 1996). Increasing NF-H in H mice brings the ratio to 0.16 (Table I). This ratio is similar to that in 6-wk-old animals (Xu et. al., 1996), yet it produces a remarkable inhibition of dendritic arborization (Figs. 1–5). Thus, our current results indicate that the delayed expression of NF-H enables dendritic growth.
The outcome of this study raises the question of why the ratio of NF-H to NF-L increases as neurons develop to maturity. The early appearance and enrichment of NF-L and NF-M in neuronal processes suggests that NFs play a role in the early development of these processes (Cochard and Paulin, 1984; Landmesser and Swain, 1992; Crino and Eberwine, 1996). On the other hand, neuronal maturation correlates with an increase in NF-H and slowing of axonal transport (Willard and Simon, 1983). Therefore, the increase in the level of NF-H may increase the stability of cytoskeleton and thereby stabilize neuronal structure in mature neurons (Willard and Simon, 1983). Collectively, the existing experimental data suggests the following sequence of events during development: as NF-H increases, the interaction between NFs and microtubules weakens, and the interaction among NFs themselves strengthens. This leads to an extensive cross-bridge formation among NFs (Hirokawa et al., 1984) and slower transport of cytoskeletal components (Willard and Simon, 1983). As these changes proceed, a stable NF matrix within axons and dendrites (particularly proximal dendrites) is formed and neuronal processes stabilize. Thus, neurons may regulate the ratio of NF-H to NF-L in order to maintain a balance between plasticity and stability of neuronal processes during different stages of development. Such a process is perhaps most relevant in large NF-rich neurons with long axons and long dendrites radiating from their cell bodies (such as motor neurons and Betz cells). The role of neurofilaments in the development of dendritic trees with short branches may be less significant. Consistent with this view, small neurons that do not have long dendritic trees and large neurons with numerous but short segmental dendritic branches (e.g., Purkinje cells) express little neurofilaments. Taken together, our results show that NFs play an important role in the development of large dendritic trees with long segmental branches.
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Submitted: 1 August 1997
Revised: 5 January 1998
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