Abnormal rate of granule cell migration in the cerebellum of “weaver” mutant mice

doi:10.1016/0012-1606(72)90039-5

Developmental Biology

Volume 29, Issue 1, September 1972, Pages 17-26

https://doi.org/10.1016/0012-1606(72)90039-5 Get rights and content

Abstract

“Weaver,” a neurological disorder in mice is transmitted by an incompletely dominant gene. Both the heterozygous carrier and homozygous weaver mice show alterations in the cytoarchitectonics of the cerebellum. However, no behavioral abnormalities of cerebellar disorder can be detected in the heterozygous carrier. Studies with autoradiography showed that the alterations in the cytoarchitectonics of both the heterozygous carrier and homozygous weaver cerebellums are associated with a reduced rate of granule cell migration.

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Cited by (201)

Interactions Between Purkinje Cells and Granule Cells Coordinate the Development of Functional Cerebellar Circuits
2021, Neuroscience
Cerebellar development has a remarkably protracted morphogenetic timeline that is coordinated by multiple cell types. Here, we discuss the intriguing cellular consequences of interactions between inhibitory Purkinje cells and excitatory granule cells during embryonic and postnatal development. Purkinje cells are central to all cerebellar circuits, they are the first cerebellar cortical neurons to be born, and based on their cellular and molecular signaling, they are considered the master regulators of cerebellar development. Although rudimentary Purkinje cell circuits are already present at birth, their connectivity is morphologically and functionally distinct from their mature counterparts. The establishment of the Purkinje cell circuit with its mature firing properties has a temporal dependence on cues provided by granule cells. Granule cells are the latest born, yet most populous, neuronal type in the cerebellar cortex. They provide a combination of mechanical, molecular and activity-based cues that shape the maturation of Purkinje cell structure, connectivity and function. We propose that the wiring of Purkinje cells for function falls into two developmental phases: an initial phase that is guided by intrinsic mechanisms and a later phase that is guided by dynamically-acting cues, some of which are provided by granule cells. In this review, we highlight the mechanisms that granule cells use to help establish the unique properties of Purkinje cell firing.
Generation and vulnerability of deep cerebellar nuclei neurons in the weaver condition along the anteroposterior and mediolateral axes
2016, International Journal of Developmental Neuroscience
Citation Excerpt :
Interestingly, the vermis is the region most severely affected, whereas cell deficit is spared in cerebellar hemispheres (Herrup and Trenkner, 1987; Eisenman et al., 1998; Maricich et al., 1997; Martí et al., 2001). In the heterozygous weavers (wv/+), neurodegeneration is less evident (Rezai and Yoon, 1972; Rakic and Sidman, 1973a,b; Herrup and Trenkner, 1987; Blatt and Eisenman, 1985; Won et al., 1997; Martí et al., 2013). In addition to cerebellum, involved in coordination of muscular activity (Trach, 2014), wv/wv exhibit progressive neurodegeneration of dopaminergic neurons in the midbrain (Triarhou et al., 1988; Martí et al., 2007b; Cavalcanti-Kwiatkoski et al., 2010).
Production and death of deep cerebellar nuclei (DCN) neurons were investigated in the weaver condition at appropriate anatomical levels throughout the mediolateral (medial, intermediate and lateral) and rostrocaudal (rostral, middle and caudal) axes of three DCN-cell groups: the fastigial, the interposed and the dentate nuclei. Current results have denoted that the deficit of DCN neurons is always more important in the homozygous weaver than in the heterozygous weaver mice. No loss of neurons was found in the dentate nucleus. In the mediolateral axis, an intranuclear gradient of depletion was observed in the mutant mice; in a given deep nucleus, neurodegeneration was more prominent in the medial pars than in lateral ones. In the rostrocaudal axis, on the other hand, when each deep nucleus was studied and compared as a whole, neuron loss was higher in the fastigial nucleus than in the interposed nucleus, which, in turn, was more important than in the dentate nucleus. These data suggest that, in the weaver condition, an internuclear gradient of neurodegeneration exists. Moreover, neurons located in rostral parts of a given nucleus appear to be more vulnerable than those settled in middle parts and these, in turn, are more than the caudal ones. These results seem to indicate the presence of an intranuclear gradient of depletion. Current autoradiographic results have revealed that, in the rostrocaudal axis, deep neurons are settled in the weaver cerebellum following three neurogenetic gradients. The first of these is internuclear; if each deep nucleus is analyzed and compared as a whole, the fastigial nucleus has more late-generated neurons than the interposed nucleus, and this, in turn, has more than the dentate nucleus. The second gradient is also internuclear; if the proportion of late-born neurons is compared throughout the rostral levels from each deep nucleus, it is observed that proportions increase from the fastigial to the dentate nucleus. A similar picture emerges when the middle and caudal regions are taken into account. The third gradient is intranuclear; in a given deep nucleus, the rostral region always presents more late-produced neurons than the middle region and these, in turn, more than in the caudal level.
Trisomy 21 and early brain development
2012, Trends in Neurosciences
Trisomy for human chromosome 21 (Hsa21) results in Down syndrome (DS). The finished human genome sequence provides a thorough catalog of the genetic elements whose altered dosage perturbs development and function in DS. However, understanding how small alterations in the steady state transcript levels for <2% of human genes can disrupt development and function of essentially every cell presents a more complicated problem. Mouse models that recapitulate specific aspects of DS have been used to identify changes in brain morphogenesis and function. Here we provide a few examples of how trisomy for specific genes affects the development of the cortex and cerebellum to illustrate how gene dosage effects might contribute to divergence between the trisomic and euploid brains.
The Vps33a gene regulates behavior and cerebellar Purkinje cell number
2009, Brain Research
Citation Excerpt :
Consequently, Purkinje neurite loss is associated with ataxia (abnormal posture and gait phenotypes) (Oppenheimer, 1984; Walton, 1985). There are a number of mouse mutants with Purkinje neuropathies, ataxia and tremors (Caddy and Biscoe, 1979; Caddy and Sidman, 1981; Heckroth et al., 1989; Herrup and Trenkner, 1987; Mullen et al., 1976; Rizai, 1972; Sonmez and Herrup, 1984; Wassef et al., 1987; Yuasa et al., 1993), all of which have provided insights into Purkinje cell development and function. Vps54, a member of the Vps family mutated in the wobbler (wr/wr) mouse, severely compromises motoneuron survival (Schmitt-John et al., 2005) and causes abnormal motility on a wire grid, weight loss and low grip strength.
A mutation in the Vps33a gene causes Hermansky–Pudlak Syndrome (HPS)-like-symptoms in the buff (bf) mouse mutant. The encoded product, Vps33a, is a member of the Sec1 and Class C multi-protein complex that regulates vesicle trafficking to specialized lysosome-related organelles. As Sec1 signaling pathways have been implicated in pre-synaptic function, we examined brain size, cerebellar cell number and the behavioral phenotype of bf mutants. Standardized behavioral tests (SHIRPA protocols) demonstrated significant motor deficits (e.g., grip strength, righting reflex and touch escape) in bf mutants, worsening with age. Histological examination of brain revealed significant Purkinje cell loss that was confirmed with staining for calbindin, a calcium binding protein enriched in Purkinje cells. This pathologic finding was progressive, as older bf mutants (13–14 months) showed a greater attrition of neurons, with their cerebella appearing to be particularly reduced (~ 30%) in size relative to those of age-matched-control cohorts. These studies suggest that loss of Purkinje neurons is the most obvious neurological atrophy in the bf mutant, a structural change that generates motor coordination deficits and impaired postural phenotypes. It is conceivable therefore that death of cerebellar cells may also be a clinical feature of HPS patients, a pathological event which has not been reported in the literature. In general, the bf mutant may be a potentially new and useful model for understanding Purkinje cell development and function.
Spontaneous and induced mouse mutations with cerebellar dysfunctions: Behavior and neurochemistry
2007, Brain Research
Citation Excerpt :
In normal adult mouse brain, Girk2 mRNA and protein levels were detectable in cerebellar granule and Purkinje cells, substantia nigra pars compacta, ventral tegmentum, and olfactory tubercle, as well as dentate gyrus and pyramidal cells of the hippocampal formation (Lauritzen et al., 1997; Murer et al., 1997; Schein et al., 1998). In cerebellum, the main depleted cell type is the granule cell (Hirano and Dembitzer, 1973; Rezai and Yoon, 1972; Sotelo, 1975). Studies with mutant chimeras indicate that the granule cell is a direct target of the mutated gene (Goldowitz, 1989; Goldowitz and Mullen, 1982).
Grid2^Lc (Lurcher), Grid2^ho (hot-foot), Rora^sg (staggerer), nr (nervous), Agtpbp1^pcd (Purkinje cell degeneration), Reln^rl (reeler), and Girk2^Wv (Weaver) are spontaneous mutations with cerebellar atrophy, ataxia, and deficits in motor coordination tasks requiring balance and equilibrium. In addition to these signs, the Dst^dt (dystonia musculorum) spinocerebellar mutant displays dystonic postures and crawling. More recently, transgenic models with human spinocerebellar ataxia mutations and alterations in calcium homeostasis have been shown to exhibit cerebellar anomalies and motor coordination deficits. We describe neurochemical characteristics of these mutants with respect to regional brain metabolism as well as amino acid and biogenic amine concentrations, uptake sites, and receptors.
Expression of amino acid receptors and neural peptides in the weaver mouse brain
2007, Brain Research
Citation Excerpt :
In the cerebellum of homozygotes weaver mice (wv/wv), granule cell neurons die soon after birth as they fail to differentiate and migrate into the internal granule cell layer. Large numbers of granule cells are lost as well as less numbers of Purkinje cells and neurons in the deep nuclei of the cerebellum, producing the prominent ataxia, characteristic of these animals (Patil et al., 1995; Rakic and Sidman, 1973; Rezai and Yoon, 1972; Triarhou, 2002). Furthermore, the weaver mutant mouse (wv/wv) represents the only natural noninvasive animal model of progressive dopamine (DA) deficiency.
In the present study, we conducted: (i) in situ hybridization in order to investigate the expression of kainate and GABA_A receptor subunits and the pre-proenkephalin and prodynorphin peptides in the brain of weaver mouse (a genetic model of dopamine deficiency) and (ii) immunocytochemistry in order to study the somatostatin-positive cells in weaver striatum. Our results indicated: (i) increases in mRNA levels of KA2 and GluR6 kainate receptor subunits, of α₄ and β₃ GABA_A receptor subunits and of pre-proenkephalin and prodynorphin in 6-month-old weaver striatum; (ii) a decrease in α₁ and β₂ GABA_A subunit mRNAs in 6-month-old weaver globus pallidus; (iii) increases in KA2, α₄ and β₃ and decreases in α₂ and β₂ mRNAs in the 6-month-old weaver somatosensory cortex; and (iv) an increase in somatostatin-immunopositive cells in 3-month-old weaver striatum. We suggest that: (i) in striatum, the alterations are induced by the induction of the transcription factor ΔfosB (for GluR6, pre-proenkephalin and prodynorphin mRNAs) and the suppression of transcription factors like NGF-IB (nerve growth factor inducible B; for the KA2 mRNA), in response to dopamine depletion; (ii) in striatum and cortex, the alterations in the expression of the GABA_A subunits indicate an increase of extrasynaptic versus a decrease of synaptic GABA_A receptors; and (iii) in globus pallidus, the increased striatopallidal GABAergic transmission leads to a decrease in the number of GABA_A receptors. Our results further clarify the regulatory role of dopamine in the expression of amino acid receptors and striatal neuropeptides.

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^☆: Part of this work was extracted from a thesis submitted by the senior author in partial fulfillment of the Ph.D. requirement at Boston College. This work was supported by Grants 5 R01 NSO2267-10, 11 awarded to the junior author by the National Institute of Neurological Diseases and Blindness. The authors wish to express their gratitude to Mrs. J. Yoon for her preparation of some of the histological slides.

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Full paperAbnormal rate of granule cell migration in the cerebellum of “weaver” mutant mice☆

Abstract

Exp. Neurol

H3-thymidine autoradiographic studies on the cell proliferation and differentiation in the external and the internal granular layers of the mouse cerebellum

J. Comp. Neurol

Full paper
Abnormal rate of granule cell migration in the cerebellum of “weaver” mutant mice☆

H³-thymidine autoradiographic studies on the cell proliferation and differentiation in the external and the internal granular layers of the mouse cerebellum