Catalog of the Neurological Mutants of the Mouse [Reprint 2014 ed.] 9780674424326, 9780674424265

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CATALOG OF THE NEUROLOGICAL MUTANTS OF THE MOUSE

Richard L. Sidman, M. D. Laboratory of Cellular Neuropathology Harvard Medical School and The Joseph P. Kennedy, Jr., Memorial Laboratories of the Neurological Services, Massachusetts General Hospital Boston, Massachusetts

Margaret C. Green, Ph. D. The Jackson Laboratory, Bar Harbor, Maine

Stanley H. Appel, M. D. Departments of Medicine and Neurology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania

Harvard University Press Cambridge, Massachusetts 1965

φ

Copyright 1965, by the President and Fellows of Harvard College All rights reserved Distributed in Great Britain by Oxford University Press, London

Part of the publication cost was defrayed by Grant No. NB 05750 from the National Institutes of Health, Bethesda, Maryland.

Library of Congress Catalog Card Number 65-28362 Printed in the United States of America

CONTENTS

Introduction

1

Mutants

9

References

71

Table 1.

Neurological mutants of the mouse

2

Table 2.

A rough classification of neurological mutants

4

Figure 1.

Linkage map of the mouse

7

INTRODUCTION

The number of mutations affecting the nervous system in mice is large and is increasing. Investigators are beginning to use these mutants für studies of many types. This is a suitable time to pull together widely diffused information on the origin, genetics, clinical characteristics, chemistry, and pathology of these mutants. Our aim is to help investigators to learn quickly and conveniently what has been done so far. If our estimate of the growing interest is accurate, and if this review helps to make the subject accessible and attractive, it may never again be as feasible as now to prepare such a catalog. Considerable information on neurological mutants in several species is available in earlier more general reviews, especially in the monographs of GrUneberg (1952, 1963) and Nachtsheim (1958). A major source of information is the informal mimeographed document, Mouse News Letter (referred to as MNL in the text). It is issued twice a year. Each issue contains a complete list of the mutants of the mouse and information from various laboratories on new mutants, research stocks, and research news. It is currently edited by Dr. M. F. Lyon and is distributed by the International Committee on Laboratory Animals, and Laboratory Animals Centre, M. R. C. Laboratories, Woodmansterne Road, Carshalton, Surrey, England. In addition to the published literature and Mouse News Letter, we have also used data from an informal mimeographed listing distributed by The Jackson Laboratory (Dickie 1958), personal communications including work presented at an International Conference on Neurological Mutants held at Bar Harbor, June 29-July 1, 1965, and some of our own previously unpublished data. The neurological mutants described here are listed alphabetically by gene symbol in Table 1. Table 2 gives a rough classification of neurological mutants. The mutants may appear in more than one category of Table 2, and many are omitted for lack of adequate information about them, though they are in some respects the ones most deserving of attention. The list of references is intended to be complete for work published since GrUneberg's (1952) monograph and contains selected earlier references. A few references on ancillary topics are given in this introduction and in the main text; all references in the bibliography pertain directly to neurological mutants in the mouse. References are cited by number in Table 1 and by name and year in the text. When there is more than one reference with the same name and year, the number of the reference is given following the year. The conventions for naming and symbolizing mutants may be found in a list of rules for genetic nomenclature prepared by the Committee on Standardized Genetic Nomenclature for Mice: A revision of the standardized genetic nomenclature for mice, J. Hered. 54:159-162, 1963. To be considered a new mutation a newly discovered mutant must be shown by appropriate genetic tests not to be allelic with other similar mutants, or if allelic, to have a different phenotypic effect from other known alleles at that locus.

1

Table 1. Neurological mutants of the mouse (arranged alphabetically by gene symbol). Gene name

Gene symbol

Linkage group

_

References

ac

absent corpus callosum

ag. av ax

agitans Ames waltzer ataxia

bh

brain hernia

cb Cd eh et

cerebral degeneration crooked congenital hydrocephalus curly-tail

d dis De dn dr dt

dilute-lethal dilute 15 dancer deafness dreher dystonia musculorum

du dv

ducky dervish

II

db

eye-blebs

IV

El

EL

epilepsy eyeless

fa fi Fu F^i

falter fidget fused kinky

V IX IX

175; 234 17; 18; 26; 47; 91; 216; 220; 221 62; 63; 84; 184; 213 29; 62; 63; 83; 84

Gy

gyro

XX

Lyon, MNL 32:30, 1960; 24:34, 1961

hy-1 hy-2 hy-3

hydrocephalus-1 hydrocephalus-2 hydrocephalus-3 hydrocephalus-like

je ji jo ÏE

jerker jittery jolting jimpy

kr Kw

kreis 1er kinky-waltzer

la

leaner

Lc lh Lp Is ni nu

lurcher leukencephalosis lethargic loop-tail lethal spotting lumbarless microphthalmia brindled muted blebs ocular retardation

III IV XV -

_ χ:ν -

II II -

XIII XIII

-

-

_

-

-

X XX V

134; 139; 140; Keeler MNL 1:3, 1949; Wimer, MNL 33:32, 1965 113; 161; 182 Schaible, MNL 15:29, 1956; 24:38, 1961; 28:39, 19 38; 79; 157; 158; 187 11; 12 50; 89; 84; 95;

218 162; 170 92; 94; 180 99

39; 40; 58; 137; 138; 167; 168; 183; 188; 191 Phillips, MNL 24:34, 1962 Lane, MNL 19:25, 1958; 22:38, 1960 48; 141 15; 16; 47; 70; 72; 73; 74; 84; 96; 112; 160 59; 60; 79: 84; Lane, MNL 19:24, 1958; 20:37, 195 Falconer and Isaacson, MNL 32:31, 1965 79; 86; 167; 168; 187; 202 Russell, MNL 17:87, 1957; 25:64, 1961 Hummel and Chapman, MNL 23:34, 1960; 28:32, 1963 and personal comm. 118; 148; 173; Imaizumi, MNL 29:89, 1963; 31:57, 6; 7; 8; 9; 10; 33; 34; 84

22; 35; 36; 84; 93 36; 236 13; 91 Mauer, MNL 29:92, 1963; 31:59, 1964 1; 42; 78; 100; 141; 222 51; 79; 106; 167; 201 Dickie, MNL 32:44, 1965 79; 179; 194; 196; 219; 224 46; 84; 109; 110; 111; 112 Gower and Cupp, MNL 19:37, 1958; Russell, MNL 25:64, 1961 Dickie, MNL 27:37, 1962; 28:35, 1963; Sidman, MNL 32:37, 1965

XI

XIII V XI XX

181

75; 76 Dickie, MNL 30:31, 1965 84; 200; 203; 207; 208; 209 164; Phillips, MNL 21:39 and personal comm. 85 84; 93; 109; 171a 81; Falconer, MNL 15:24, 1956 Lyon and Meredith, MNL 32:38, 1965 4; 5; 27; 28; 93 144, 145; 146; 147; 217

Table 1 (continued) Gene name

Gene symbol

Es Ei Ei

pink-eyed sterile pallid pirouette pivot

Linkage group I V XVII -

-

ai

quinky quaking quivering

r

rodless retina

rd

retinal degeneration

XVII

ri

reeler

XVII

s S7

piebald piebald-lethal staggerer shaker-1 shaker-2 shaker-3 shambling splotch delayed splotch spastic spinner shaker-short surdescens Snell's waltzer shaker-withsyndactylism

Q ak

ÎS. sh-l sh-2 Sh-3 shm

spa sr 5t 5U 5V

ai tb td

Ê& th ti tm tn [r

tumbler torpid tottering tilted head tipsy tremulous teetering

[w

trembler tremor twirler

Λ

unbalanced

/

waltzer deaf varitint-waddler vibrator vacillans waddler writher

7df Ja ώ !C tfd vh vi ii

nr Vt vv

whirler wabbler-lethal wobbler waltzer-type weaver zigzag

-

I IV

III III II I VII -

XIII XIII -

II -

_ II XVIII XIII VII -

VII VII -

XV -

χ χ

References

40; 90; 17; 18; 41; 43; Dickie,

114 30; 69; 93; 155; 156; 185; 186 54; 55; 79; 141; 225 personal comm.

Schaible, MNL 20:34, 1959; 24: 38, 1961 194; 219 165; 227; 228; 230; 232; 233 115; 116; 117; 125; 126; 127; 128; 129; 130; 131; 132; 135; 136; 195; Keeler, MNL 1:3, 1949 19; 24; 25; 56; 65; 77; 80; 102; 119; 120; 121; 1 123; 124; 151; 153; 154; 174 ; 176; 177; 178; 19 195; 205; 210; 211; 212; 235 67; 68; 79; 103; 104; 105; 166 ; 167; 168 14; 64; 163 Lane, MNL 26:35, 1962 187; 197; Lane, personal comm. 43; 90; 93; 101; 141; 152; 169 ; 237 42; 57; 66; 71; 93; 141; 204 Gates, MNL 32:82, 1965 Sidman, personal comm. 3; 52; 84; 189; 203; Hollander , MNL 20:34, 1959 52 31; 32; 79; 167; 168; 187 49 20; 21; 61; 84; 93 45; 142; 143 Green, MNL 23:34, 1960; 28:32, 1963 45; 97; 98; 99; 109; 112

Dickie, MNL 32:45, 1965 Dickie, MNL 32:45, 1965 87; 88; 167; 187 Kelly, MNL 19:37, 1958; Larsen , MNL 33:69, 1965 192 230; 231; 232 167; Lane, MNL 23:35, 1960; 27 :38, 1962 and personal comm. 23; 67; 71 Truslove, MNL 30:38, 1964 79; 158; Lyon, MNL 32:39, 1965 Lyon and Meredith, MNL 32:38, :1965

-

43; 79; 82; 93; 133; 141; 201; 226 44; 141 37; 42; 141 Lane, MNL 32:47, 1965 182; 198; 199 227; 229; 230; 231; 232 Kelly, MNL 8 (suppl):15, 1953; Russell MNL 17:87, 1957; 19:36, 1958 149; 190; 223 2; 53; 107; 108; 150; 171; 187 ; 214; 215 Falconer, MNL 15:23, 1956 206 Lane, MNL 30:32, 1964

-

159; Lyon, MNL 29:37, 1963

XVI -

Vili Vili -

Vili III -

Table 2.

A rough classification of neurological mutants.

Dysraphic Disorders

(craniorachischisis with failure of dorsal fusion in brain and cord, and incomplete variants, including anencephaly, pseudencephaly, myeloschisis, etc.) Blebs (m¿) ; Crooked (Cd); Curly-tail (ct); Fused (Fu); Kinky (Fu ki ); Loop-tail (L£) ; Quinky (¿) ; Shaker-3 (Sh-3); Splotch (S¿). Neural Crest Disorders

(expressed as deficiency of ganglion cells in wall of gut with resultant megacolon, or as failure to form dorsal root ganglion cells, with or without pigmentation defects) Dreher (dr) ; Lethal spotting (Is); Piebald (s) ; Piebald-lethal (s^); Splotch (SjO. Microphthalmia or Anophthalmia

(omitting mutants that affect primarily nonneural parts of eye) Blebs (my); Brain hernia (bh); Congenital hydrocephalus (ch); Eye-blebs (eb); Eyeless (ey); Fidget (fi); Microphthalmia (mi); Ocular retardation (or). Cerebellar Malformations Leaner (la) ; Reeler (ri) ; Staggerer (sg) ; Weaver (wv) .

Hydrocephalus (various types) Brain hernia (bh); Cerebral degeneration (cb); Hydrocephalus-1 (hy-1); Hydrocephalus-2 (hy-2); Hydrocephalus-3 (hy-3); Hydrocephalus-like; Leukencephalosis. Embryonic Inner Ear Malformations Dancer (De) ; Dreher (dr) ; Fidget (fi); Kreis 1er (kr); Muted (mu); Pallid (£a); Shaker-short (st) ; Shaker-with-syndactylism (s¿); Surdescens (su); Twirler (Tw); Unbalanced (ub); Waltzer-type (Wt). Postnatal Inner Ear Degenerations (Neuroepithelial Dystrophies) Ames waltzer (av) ; Deaf (v«) ; Deafness (dn) ; Gyro (G¿) ; Jerker (je) ; Pirouette (£i) ; Pivot; Shaker-1 (sh-1); Shaker-2 (sh-2) ; Snell's waltzer (sv); Spinner (sr); Varitint-waddler (Va); Waltzer (v); Whirler (wi). Inner Ear Mutants of Unknown Type Dervish (dv); Kinky-waltzer (Kw); Quinky (£); Shaker-3 (Sh-3); Tilted head (th).

Table 2

(continued)

Mutants with Pathological Changes in the Nervous System a Absent corpus callosum (ac); Ataxia (ax); Cerebral degeneration (cb); Dilute lethal (ci) ; Dystonia musculorum (dt) ; Eyeless (ey) ; Fidget (fi) ; Jimpy (jp); Leaner (la); Leukencephalosis; Quaking (qk); Reeler (ri); Staggerer (sg); Shaker-with-synd&ctylism (sy); Wabbler-lethal (wl); Weaver (wv).

Epileptic Seizures (various types)'' Dilute lethal ( •Η Λ λ -ρ υ

,

%

%

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- · — — h h · , , SO i l o M i t

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S fr I S S β 0) û) +J g m S Ί3 u m < . ' S I I I III ν « ν oj-

S £

h- ' i n

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w

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JS Ρ ρ

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CVH β ΙΛ ι—I

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MUTANTS

Absent corpus callosmn, ac, recessive This mutation was first recognized by Keeler (1933) in descendants of a cross between rodless (r)and silver (si) strains. In the course of anatomical studies on visual areas of the central nervous system of rodless animals, the incidental observation of absent corpus callosum was made (King and Keeler 1932). A sample of eleven Bagg albino mice, the original stock from which r was derived, were normal, as were a number of other inbred strains (King and Keeler 1932) . The mutant gene ac is probably not linked to r or si (linkage group IV) or to W (linkage group XVII). No clinical signs of the disorder were recognized. The anatomical pathology has been examined in adult affected mice and was found to be very similar to many adult human cases. The two main features are complete or partial absence of the corpus callosum and the presence in each hemisphere of a longitudinal callosal bundle (Balkenlangsbundel), whose myelinated fibers arise in the cortical gray matter and run sagittally in the ipsilateral hemisphere instead of crossing the midline in early fetal life. There are three anatomical types in the mouse, each with slight variations (King 1936): 1. Complete absence of corpus callosum; 2. A partial, atypical callosum in the anterior portion of the brain; and 3. A partial corpus callosum present posteriorly. These different types do not breed absolutely true. Litters from parents both of whom are defective may in occasional instances include perfectly normal mice, and if abnormal, the type of defect may be different from that possessed by the parents. The longitudinal callosal bundle, or simply longitudinal bundle, is a striking feature of the mutants' brains. In frontal sections, it appears as a compact myelinated bundle in the dorsomedial portion of each hemisphere. The fibers course in a swirling, disorderly fashion, but run predominantly anteroposterior^. Heavily myelinated fibers in it are derived from lateral cortical areas and finer, more lightly myelinated ones arise from medial and frontal cortex. From the longitudinal bundle, strongly myelinated fibers pass downward in a curving course to terminate in the septum. Some join the fornix, and pass either in front of the anterior commissure or behind it into the hypothalamus and thalamus. Many of these fibers apparently correspond to the fibers that perforate the corpus callosum roughly at right angles to the direction of the callosal fibers in the normal brain. In the more anterior portions, some fibers leaving the longitudinal bundle approach the hippocampal commissure, but apparently do not actually cross the midline. These fibers are variable' in number and always asymmetrical between the two hemispheres; they may represent an abortive attempt at the formation

9

of corpus callosum. Sometimes a considerable bundle of heavily myelinated fibers leaves the longitudinal bundle and heads medially, but stops abruptly just short of the midline (King 1936, Fig. 10). Other anatomical disturbances appear to be secondary to the primary defect in formation of the corpus callosum. The angular bundle, which arises in the entorhinal cortex, crosses the midline in a portion of the splenium of the corpus callosum designated as the dorsal psalterium. In the mutant brains the angular bundle is present but runs an abnormal course because the splenium of the corpus callosum is absent. The angular bundle passes anteromedially until it reaches the hippocampal commissure, then turns medially in the horizontal plane and crosses in an abnormally positioned commissure which contains all of the fibers of the dorsal psalterium and ventral psalterium gathered into a common structure. Another tract, the fornix longus, arises from the subiculum and posterodorsal part of the hippocampus, and proceeds forward in an aberrant course just under the longitudinal bundle. The indusium griseum is the portion of the hippocampus situated in the anterior part of the cerebral hemisphere, normally dorsal to the corpus callosum. In the mutants, it is of normal size but is tilted vertically instead of horizontally. Since it need not course over the splenium of the corpus callosum to join with the larger, more ventrally positioned part of the hippocampus, the junction takes place very directly. The hippocampus seems normal in sections stained for cells, fibers, or myelin, except for certain short myelinated fascicles running between the fascia dentata and the subiculum, without homologue in the normal mouse brain. Brains with partial corpus callosum present anteriorly differ but little from the above description. When a partial corpus callosum is present posteriorly, there is a well-marked splenium. The longitudinal bundle is present, but fibers leave its entire posterior portion, beginning just dorsal to the hippocampal commissure, and cross the midline to become continuous with the corresponding formation of the opposite side. Posteriorly they cease to cross at the level of the caudal portion of the superior thalamic radiation. The caudal extent of the corpus callosum is less than in the normal. Because a welldeveloped, atypical corpus callosum does exist posteriorly, the angular bundle, fornix longus, dorsal and ventral psalterium, and indusium griseum are almost normal. The special connections between fascia dentata and the subiculum, mentioned above, are not seen in this variant. The distribution of nerve cells in the neocortical gray matter was normal in each of the cytoarchitectonic fields described by Rose (King 1936). Probably those cortical neurons which form the corpus callosum in the normal, furnish the constituents of the longitudinal bundle in the defective animals. Many further details are given in King's (1936) report. His paper also gives one of the best descriptions available of myelinated fiber systems in the normal mouse cortex. Keeler's strain is extinct (Keeler, MNL 1:3, 1949). However, a disorder apparently identical to the one described by Keeler and King has recently been recognized in some BALB/cJ mice, and a somewhat different callosal defect in 129/J mice (Wimer 1965, MNL 33:32, 1965).

10

Agitans, ag, recessive, linkage group III This spontaneous mutation appeared in a ."rhino" stock from McGill (Hoecker et al. 1954). The clinical features are ataxia and fine tremor during activity, aggravated with increasing age until the animals die with paralysis and cachexia before or around the third month after birth. The symptoms vary in intensity at early stages, but are evident by 10 days of age. Affected animals cannot swim, and both sexes are sterile. No macroscopic abnormalities of the brain were found (Martinez and Sirlin 1955). Brains and spinal cords were fixed by immersion, serially sectioned, and stained with a number of neurohistological techniques. The cerebellum is normal in the second postnatal week but later, many atrophied Purkinje cells are seen. By 21 days, a few cells with pyknotic nuclei and overstained cytoplasm are found randomly distributed through the spinal cord. No disease was found in white matter tracts and no inflammation was noted. The authors recognized a remarkable lack of correspondence in individual adult cases between the clinical and the pathological findings. Although symptoms in the adult are always intense, lesions may or may not be present. Some animals have lesions in cerebellum and cord, some in only one of these areas, others in neither. The cell changes described in cerebellum and spinal cord may be artifacts. Such cells are commonly seen in normal specimens fixed by immersion and are much more rare when the brain is fixed by perfusion and allowed to remain undisturbed in the skull for an adequate length of time before removal for further processing. In view of this, and the lack of clinico-pathological correlation, the mutant deserves re-examination. Ames waltzer, av, recessive, linkage group IV This waltzing mutant appeared in the Κ strain at Iowa State University (Shaible, MNL 15:29, 1956) and its linkage group was established subsequently (Shaible, MNL 24:38, 1961; 28:39, 1963). Viability and fertility are about normal but females are poor mothers. The mutant is best maintained by mating av/av males with av/+ females and setting out the females when pregnant to prevent the young from being trampled to death. Homozygotes show the typical circling, head tossing, deafness, and hyperactivity of the circling mutants. They have defects of the membranous labyrinth similar to those of sh-2 (Deol 1965, personal communication). Ataxia, ax, recessive, linkage group XV This mutant arose spontaneously in 1950 in the CBA/H strain (Lyon 1955, 157). An allelic mutant initially named paralytic, now designated a)r, arose spontaneously in a kreisler stock in 1953 at The Jackson Laboratory. At 2 weeks of age, affected animals are smaller than littermates and show weakness of the extremities and trunk, most marked in the

11

hindquarters. At 3 weeks of age an affected animal has difficulty in righting itself when rolled over onto its side or back. When inside or outside the cage, the animal shows marked tremulousness involving trunk and extremities. The tremulousness is accentuated during voluntary or purposive exploratory movements and is remarkably diminished at complete repose. The gait is characterized by short shuffling steps, especially in the hindlimbs. The hindlimbs show increased resistance to passive manipulation, in addition to their weakness. Gradually the tone increases to the point where the hindlegs are firmly clasped and cannot move independent of each other. The front extremities are stiffened to a lesser degree. With attempted forward movements the animal will fall to either side as a result of the increased tone and the impaired coordination. When placed in water it supports itself by propelling movements of the trunk and clasped hindlimbs. With rapid rotation there is no accentuation of the movement disorder. By 5 weeks or later the condition has progressed to complete paralysis of hindlimbs and sufficiently altered tone in the frontlimbs so that the animal lies on its side with infrequent locomotion. With care the animals can be kept alive for many months, occasionally for a year. The animals are not deaf. They do not breed. The following account of the pathology is based on unpublished studies of ax"* (Hicks and D'Amato 1964, personal communication). Mature animals show a widespread defect in the growth of nerve cells, especially involving their axis cylinders. There is some diminution in cell number and the deep layers of the cerebral cortex appear poorly differentiated. The corpus callosum is diminished in bulk out of proportion to the small size of the brain, and the internal capsule and pyramidal tracts are reduced in size. All white matter of the spinal cord is considerably reduced, most severely in the caudal parts. In contrast, the gray matter of the mutant spinal cord is virtually the same size in cross section as the normal control cord. In late stages, axis cylinders in the white matter of the spinal cord show focal swellings, sometimes six to eight times the diameter of the normal axis cylinders; these "torpedoes" are seen in many human and animal diseases and are considered to be a nonspecific sign of disease. Glia throughout the white matter are deficient in two respects. There are fewer cells per unit volume of tissue and the cells have less basophilic staining material (RNA) in the cytoplasm than the normal controls. Hypertrophy and production of fibers by a few astrocytes, a reactive change, is seen in spinal cord white and gray matter at late stages. Disease is already evident microscopically at the time of birth. Nerve cell bodies and axons are smaller than controls, and fewer nerve cells are evident in all layers of the cerebral cortex, especially the large pyramidal cells of layer V and the smaller cells of VI. The fiber bundles of the corpus callosum, cingulum, striatum, and internal capsule are already disproportionately small. The pyramidal tract is small from the time it is first recognized in myelin-stained sections. Peripheral nerves also have smaller myelin sheaths and smaller axis cylinders than the normal controls. The vertebral column is abnormal, in that the foramina through which the spinal nerves pass are smaller than normal and the shape of the cord and vertebrae is such that the spinal nerves leave the cord in

12

a lateral rather than a ventrolateral direction. These changes are thought to be primary, rather than a consequence of the paralysis. A common denominator for the various neural and skeletal disorders has not been recognized. The cerebellum and its major tracts appear relatively free of disease. The validity of the changes described above is difficult to establish because the changes are quantitative rather than qualitative. The problem is made even more difficult because the mutant animals are generally much smaller than their normal, littermates. The progressive character of the clinical disorder has not been accounted for.

Blebs, my, recessive In a series of papers beginning in 1923, Little and Bagg described a number of heritable defects among the descendants of X-rayed mice. Penetrance is probably incomplete. The defects involved eyes, skull and brain, limbs, and skin--all thought to be late sequelae of superficial blebs in 12-day and older embryos. As indicated in the original name, myelencephalic blebs were thought to arise in the early embryo from production of excess spinal fluid that was forced out of the neural tube through the foramen anterius in the roof of the myelencephalon, to attain a position between the ectoderm and mesenchyme. Grllneberg (1952) reviews 38 papers on m^. A reanalysis of tne genetics was made by Carter (1956), who concluded that all of the common defects and probably most of the rare ones in this protean disorder are parts of a variable syndrome due to my/my, with modification on some genetic backgrounds and perhaps influenced by nongenetic factors. In 1959, Carter analyzed the embryology of my, and used different families to select for high incidence of certain manifestations. The major affections of the central nervous system are acrania and pseudencephaly. These are two forms of a common basic disease process produced in man and many animals from genetic and environmental causes. Acrania, absence of brain and dome of skull, is found only among dead newborn mice. It is not found in animals still enclosed in the amnion. Acraniate animals were considered to be pseudencephalic individuals which had lost their abnormal, exteriorized neural tissue, presumably at the time of removal from the amnion by the mother. Pseudencephaly is seen at all embryonic stages from 9 1/2 days of gestation onward. At 9 1/2 and 10 1/2 days of gestation the neural ridges fail to close in the mesencephalon or anterior part of the myelencephalon. With further growth, the whole dorsal surface of this part of the head consists of exposed neural tissue. At the same time, the closed parts of the neural tube fail to become distended and their walls have a crumpled appearance. Histological development continues. Pseudencephaly thus is a severe dysraphic state, and Carter criticizes the earlier notion that it results from an abnormal relationship between notochord and overlying neural tissue. He also makes cogent criticisms of the idea that the subcutaneous blebs in the embryo originate from spinal fluid. The variable malformations of the eye and other superficial organs are secondary to the formation of blebs, but the source of the blebs remains obscure.

13

Brain hernia, bh, recessive, linkage group I This mutant appeared spontaneously in offspring of a cross between Bar Harbor AKR and Columbia inbred "Brachy" stocks (Bennett 1959). Viability of homozygotes is reduced, but some survive and may breed well. Penetrance is probably variable and dependent upon the genetic background. At birth, bh/bh mice may have foreshortened heads and cerebral hernias, varying in severity from a barely noticeable blister to a hemorrhagic sac several millimeters in diameter. The herniated brain is always covered with skin. Some animals have hydrocephalus, and not all of these have brain hernia. About 75 percent of the bh/bh newborns have severe microphthalmia or anophthalmia. After 2 or 3 weeks of age, all homozygotes develop polycystic kidneys, but they have higher than normal levels of free amino acids and protein in the urine prior to the development of obvious kidney pathology (Bennett 1961).

Brindled, Mo

br

, semidominant, linkage group XX (sex-linked)

This sex-linked allele of mottled (Mo) arose spontaneously in the C57BL inbred strain (Fraser et al. 1953). Heterozygous females (Mo /+) have irregular patches of full-coloreg^and very light-colored fur over the whole coat. Hemizygous males (Mo /Y) and homozygous females (Mo b r /Mo b r ) are almost devoid of pigment except in the eyes and ears. They usually die when two weeks old but a few males have lived and been fertile. Hemizygotes and homozygotes show slight tremor, uncoordinated gait, and a clasping of hindlegs when held up by the tail (Falconer, MNL 15:24, 1956). The clasping is a nonspecific characteristic of many neurological mutants in mice.

Cerebral degeneration, cb, recessive This gene described by Deol and Truslove (1963) produces ex vacuo hydrocephalus which is clearly visible in the living animal. The time of onset varies, but classification is usually possible at birth. Affected animals generally die before maturity, but if they live they are always sterile. The most susceptible parts of the brain are the cerebral hemispheres and the olfactory lobes. White matter degeneration is seen in the cerebral hemispheres. In later stages the epithelium of the nose and trachea also degenerates. Abnormalities in the bone structure of the cranium are believed to be secondary. The primary disease process in the brain remains to be described. It is not known whether or not the cerebral white matter degeneration is primary. The disorder may be similar to the one described by Fischer (1959, 75, 76) under the name leukencephalosis. However, this cannot be checked by genetic testing because Fischer's mutant is now extinct.

Congenital hydrocephalus, ch, recessive, linkage group XIV This appeared as a spontaneous mutation in descendants of an outcross of the CBA inbred strain (Grllneberg 1943, 92).

14

Homozygous animals die immediately after birth, possibly from inability to inflate their lungs. Each mouse has a bulging forehead and skull, enclosing thin-walled cerebral hemispheres filled with hemorrhagic cerebrospinal fluid. The hydrocephalus is secondary to abnormal development of the cartilaginous skull (Grlineberg 1953 and 1963). The abnormality has been traced back to early embryonic stages when the condensations of mesenchyme around the base of the brain are smaller than normal. Once laid down, the cartilage grows at a normal rate, but the base of the skull remains abnormally short; the hydrocephalus is a consequence of this abnormality.

Crooked, Cd, semidominant Crooked arose spontaneously in 1947 in the A strain (Morgan 1954). The name derives from the fact that heterozygous animals have one or more crooks in the tail. In homozygous affected animals nervous head movements are common and several dysraphic abnormalities occur, including pseudencephaly, exencephaly, and anencephaly; some have microphthalmia and defects in other organs (Morgan 1954; Grewal 1962). Curly-tail, ct, probably recessive with incomplete penetrance Curly-tail arose spontaneously in the GFF inbred strain (Grlineberg 1954 and 1963). The genetic data are interpreted to indicate that ct^ is probably a recessive with incomplete penetrance (53 percent) but do not absolutely rule out the possibility that it is a dominant with reduced penetrance. Many of the presumed homozygotes die at or before birth. Survivors usually have a curly or kinky tail as a result of spina bifida of the lumbosacral vertebrae. Occasional animals have anencephaly, which is probably best interpreted as a more severe degree of the same basic dysraphic process. The skeletal abnormality, as in Loop-tail, Splotch, and perhaps Fused, may be secondary to a faulty closure of the neural tube during early embryonic development.

Dancer, De, semidominant Dancer arose spontaneously in 1956 in strain C3H/J-ob (Lane, MNL 19:25, 1958) It resembles twirler (Tw) phenotypically but is not allelic with it. Many heterozygous animals show circling behavior like waltzer (v) but have fewer head movements. They cannot swim on the surface because of the disorder of equilibrium. They are not deaf. There is complete absence of the macula of the utriculus accompanied by gross defects of the bony and membranous labyrinth (Deol 1965, personal communication). Both sexes are fertile. Homozygotes die at birth eith either bilateral or unilateral harelip or cleft palate (Lane, MNL 22:38, 1960).

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Deaf, v d f , recessive to wild-type, dominant to v, linkage group X This mutation is described after waltzer (v). Deafness, dn, recessive This mutant was discovered already widespread in a "curly-tail" stock at University College, London, in the course of a systematic search for uncomplicated deafness (Deol and Kocher 1958). Viability and fertility of homozygotes are normal. Homozygotes are deaf their entire life and a few of them show slight head tossing--a barely perceptible accentuation of the normal sniffling movements. The earliest pathological change is found on the tenth day after birth, when Deiter's cells of the organ of Corti begin to lose their identity. Degenerative changes in the hair cells are seen at 15 days. Degeneration throughout the scala media complex is advanced at 21 days but the spiral ganglion is not seen to be abnormal until about 50 days. The organ of Corti and the spiral ganglion are almost completely degenerated at 9 months. The macula of the sacculus may degenerate in both head tossing and normally-behaving mice and remains histologically normal in many of them. Dervish, dv, recessive This mutant was first described at Oak Ridge as a possibly radiationinduced "recessive waltzer" with the symbol "260 K w " (Russell, MNL 17:87, 1957). Homozygous affected animals are viable, but the phenotype has not been described in any detail (Russell, MNL 25:64, 1961). Dilute-lethal, d , recessive to wild-type and d, linkage group II This allele of dilute (d) is of outstanding interest because of certain similarities to human phenylketonuria. The first recorded àf mutation occurred spontaneously in 1951 in the C57BL strain (Searle 1952). Since then there have been numerous recurrences of mutations similar to d^. Russell and Russell (1960) have described some of these and have discussed evidence that d$ and d^ are pseudoalleles. The