Postnatal decrease in transforming growth factor α is associated with enlarged ventricles, deficient amygdaloid vasculature and performance deficits
Section snippets
Subjects
Three strains of male mice, C57BL/6J (C57), gene-targeted TGFα null mutant C57BL/6J-Tgfαtm/Ard (TGFα−/−) and APB/Le/ a/a Tyrp1b/Tyrp1b bt/bt p/p Bmp5se/Bmp5se Tgfαwa1/Tgfαwa1 (Wa-1) were obtained from the Jackson Laboratory (Bar Harbor, MA, U.S.A.). Mice were housed in a 12-h/12-h light–dark cycle with free access to food and water. Litters for analysis were produced by standard homozygous matings of each strain. Litters larger than 10 pups were trimmed. Mice were weaned at 21 days and housed
Results
Wa-1 mice are phenotypically similar to gene-targeted TGFα−/− null mutants in that each have wavy coats and exhibit ocular abnormalities. The Wa-1 mice, unlike the gene-targeted nulls or C57 mice, exhibit enlarged lateral ventricles (Fig. 1) and show reduced fear conditioning (Figs 8 and 9). Qualitatively, brains of the Wa-1 mice appeared normal and contained gross structures of the olfactory bulbs, neocortex, hippocampus, basal ganglia, septum, thalamus, brainstem and cerebellum. Nissl-stained
Discussion
In the present study, we investigated the potential role of TGFα in maintaining the morphological and vascular integrity of the limbic system. To do so, we studied three strains of mice: the gene-targeted TGFα null mutant, which completely lacks TGFα from the onset of development; the naturally occurring mutant Wa-1, which has a reduction in TGFα in adulthood; and the C57/BL6J strain, which has a normal complement of TGFα.
Conclusion
The present results demonstrate that the Wa-1 animal, a hypomorphic mutant, has a CNS phenotype distinct from the TGFα−/− null mutant, including late-onset enlargement of the lateral ventricles, loss of nuclear volume and vascular alterations in the amygdala, accompanied by age-related behavioral deficits. The late adolescent onset of the selective loss of function in the Wa-1 mouse may be due to initial and adequate levels of growth factor during development, followed by a reduction in growth
Acknowledgements
We would like to thank Lindsey Lair and Eric Parsons for expert technical assistance. This work was supported by NIMH 45507 and NIDA 09555 (to P.L.), NIMH MH59970 and IBN 9511-27 (to T.J.S.), and a predoctoral NRSA MH10777 (to R.C.B.).
References (58)
- et al.
Trophic actions of transforming growth factor alpha on mesencephalic dopaminergic neurons developing in culture
Neuroscience
(1993) - et al.
Response diversity and the timing of progenitor cell maturation are regulated by developmental changes in EGFR expression in the cortex
Neuron
(1997) - et al.
Mechanisms of emotional arousal and lasting declarative memory
Trends Neurosci.
(1998) Unusual behavioral phenotypes of inbred mouse strains
Trends Neurosci.
(1996)Transforming growth factor alpha
Cell
(1988)- et al.
Linkage of the murine transforming growth factor-alpha gene with Igk, Ly-2, and Fab p1 on chromosome 6
Genomics
(1993) - et al.
The role of the amygdaloid central nucleus in the retention of differential Pavlovian conditioning of bradycardia in rabbits
Behav. Brain Res.
(1986) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype?
Trends Neurosci.
(1996)The contribution of the amygdala to learning and performance of conditioned fear
Physiol. Behav.
(1992)- et al.
Amygdala central nucleus lesions: effect on heart rate conditioning in the rabbit
Physiol. Behav.
(1979)
The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF-beta superfamily
Cell
The amygdala: contributions to fear and stress
Semin. Neurosci.
TGF-α deficiency results in hair follicle and eye abnormalities in targeted and waved-1 mice
Cell
Mice with a null mutation of the TGF alpha gene have abnormal skin architecture, wavy hair, and curly whiskers and often develop corneal inflammation
Cell
Regional expression of transforming growth factor-α mRNA in the rat central nervous system
Neurosci. Lett.
Striatal TGF-alpha: postnatal developmental expression and evidence for a role in the proliferation of subependymal cells
Brain Res. devl Brain Res.
A gene for eyelids open at birth in the house mouse
Nature, Lond.
Characterization of the mouse transforming growth factor alpha gene: its expression during eyelid development and in Waved 1 tissues
Cell Growth Diff.
Innate and conditioned reactions to threat in rats with amygdaloid lesions
J. comp. physiol. Psychol.
Transforming growth factor alpha in developing rats
Am. J. Physiol.
Late onset morphological changes in the brain of a TGF-alpha deficient mouse, Waved-1
Molec. Biol. Cell, Suppl.
A new eye abnormality in the house mouse
J. Hered.
Transforming growth factor alpha, but not epidermal growth factor, promotes the survival of sensory neurons in vitro
J. Neurosci.
Waved: an autosomal recessive coat form character in the mouse
J. Genet.
Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm
Behav. Neurosci.
The role of the amygdala in fear and anxiety
A. Rev. Neurosci.
Mechanisms specifying area fate in cortex include cell-cycle-dependent decisions and the capacity of progenitors to express phenotype memory
Development
Localization of cells containing transforming growth factor-alpha precursor immunoreactivity in the basal ganglia of the adult rat brain
Growth Factors
Lesions of the central nucleus of the amygdala block conditioned excitation but not conditioned inhibition of fear as measured with the fear potentiated startle effect
Behav. Neurosci.
Cited by (19)
Loss of Thr286 phosphorylation disrupts synaptic CaMKIIα targeting, NMDAR activity and behavior in pre-adolescent mice
2011, Molecular and Cellular NeuroscienceCitation Excerpt :In contrast, the ratio of GluN1 and GluN2B to CaMKIIβ in the immune complexes was not significantly different between T286A-KI and WT mice (not shown). It is well established that genetic alterations of the expression or function of developmentally important molecules can result in complex age-dependent phenotypes and neuroadaptive changes (see for example, (Adusei et al., 2010; Burrows et al., 2000); reviewed in (Thompson and Stanwood, 2009)). Changes of CaMKII isoform expression levels or CaMKII interactions with NMDAR GluN2B subunits disrupt synaptic development and plasticity in neuronal cultures (Barria and Malinow, 2005; Thiagarajan et al., 2002; Wu and Cline, 1998).
ErbB receptor signaling in astrocytes: A mediator of neuron-glia communication in the mature central nervous system
2010, Neurochemistry InternationalCitation Excerpt :The neuroendocrine control of reproduction in the hypothalamus provides an integrated example of how astrocytic ErbB receptor signaling coordinates neuron-to-astrocyte and astrocyte-to-neuron interactions governing a physiological function in the mature brain. In a broader context, these data raise the intriguing possibility that the orchestration of neuron-glia communication by astrocytic ErbB signaling mediates other fundamental physiological functions of the adult CNS that involve ErbB signaling, such as the response to stress (Burrows et al., 2000; Hilakivi-Clarke et al., 1993, 1992; Koshibu et al., 2005) and locomotor and feeding behaviors (Snodgrass-Belt et al., 2005). Moreover, the increasingly recognised role of astrocytes to the course of many neurological disorders, as well as the frequent dysregulation of erbB signaling in these pathological situations, suggest that exploration of the astrocytic erbB signaling may be interesting from a pathogenic and therapeutic perspective.
Enlarged lateral ventricles and aberrant behavior in mice overexpressing PDGF-B in embryonic neural stem cells
2010, Experimental Cell ResearchCitation Excerpt :Enlargement of the lateral ventricles, as those detected in the nes/tk-Pdgfb-lacZ transgenic mice, has been associated with several abnormalities in other transgenic mouse models. For example, the waved-1 mutant, in which TGF-β levels decrease postnatally, develops enlarged lateral ventricles, which coincide with a performance deficit in fear conditioning [38]. Additionally, mice with deficits in neural migration, such as the NCAM-180 knockout mice, have a marked increase in the size of the lateral ventricles and a reduced prepulse inhibition of startle [39].
Expression of Tgfα in the suprachiasmatic nuclei of nocturnal and diurnal rodents
2007, NeuroscienceCitation Excerpt :This result is somewhat unexpected and a thorough investigation of these waved-2 mice conducted by Mrosovsky and colleagues (2005) led them to conclude that these mice do not show any gross defect in locomotor activity and in direct inhibiting effects of light on locomotor activity (so-called, masking to light), contrary to what was previously reported (Kramer et al., 2001). Furthermore, in Tgfα−/− null mutant mice, the basal locomotor activity in an open field is not different from that of wild-type mice (Burrows et al., 2000). Altogether, these data question the proposed role for TGFα in the inhibition of locomotor activity.
Making the Case for a Candidate Vulnerability Gene in Schizophrenia: Convergent Evidence for Regulator of G-Protein Signaling 4 (RGS4)
2006, Biological PsychiatryCitation Excerpt :The opportunity to analyze the role of RGS4 utilizing ‘genetically titrated’ expression is quite exciting. Based on our previous work with transforming growth factor-α gene, in which a complete deletion of the gene yields a much less robust phenotype than a hypomorphic state of gene expression (Burrows et al 2000; Koshibu et al 2005), we anticipate that the hypomorphic and null RGS4 targeted lines also will exhibit distinct phenotypes. This opportunity is particularly relevant for modeling in mice some aspects of the pathophysiology of a human disease like schizophrenia, as disease vulnerability is not likely to be due to complete loss of function of these genes.
- *
Present address: Department of Radiology, Box 356004, University of Washington School of Medicine, Seattle, WA 98195, U.S.A.