Cellular distribution of the fragile X mental retardation protein in the mouse brain

Abstract

The fragile X mental retardation protein (FMRP) plays an important role in normal brain development. Absence of FMRP, caused by transcriptional silencing of FMR1 gene, results in abnormal neuronal morphologies in a selected manner throughout the brain and leads to intellectual deficits and sensory dysfunction in the fragile X syndrome (FXS). Despite the paramount importance of FMRP for proper brain function, its overall expression pattern in the mammalian brain at the resolution of individual neuronal cell groups is not known. In this study, we used FMR1 knockout and their isogenic wild type mice to systematically map the distribution of FMRP expression in the entire mouse brain. Using immunocytochemistry and cellular quantification analyses, we identified a large number of prominent cell groups expressing high levels of FMRP at the subcortical levels, in particular sensory and motor neurons in the brainstem and thalamus. In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels. More importantly, we describe differential patterns of FMRP distribution in both cortical and subcortical brain regions. Almost all major brain areas contain high and low levels of FMRP cell groups adjacent to each other or between layers of the same cortical areas. These differential patterns indicate that FMRP expression is specific to individual neuronal cell groups, instead of associated with brain regions as previously considered. Taken together, these findings support the notion that FMRP mechanisms of neuronal regulation are cell-type specific and strongly implicate the contribution of fundamental sensory and motor processing at subcortical levels to FXS pathology.

Mechanisms underlying auditory processing deficits in Fragile X syndrome

“…Recent cellular analyses, however, reported strong expression of FMRP in auditory brainstem cell groups across a number of vertebrate species . Quantitative analyses across the entire adult (5‐6 weeks) mouse brain further confirmed that auditory neurons in the brainstem and thalamus have levels of FMRP immunoreactivity comparable to those in cortical neurons . It is worth noting that FMRP is also expressed in spiral ganglion neurons, which convey acoustic signals from the inner ear to the brainstem, in both birds and mammals.…”

“…It is worth noting that FMRP is also expressed in spiral ganglion neurons, which convey acoustic signals from the inner ear to the brainstem, in both birds and mammals. In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels …”

“…27 Quantitative analyses across the entire adult (5-6 weeks) mouse brain further confirmed that auditory neurons in the brainstem and thalamus have levels of FMRP immunoreactivity comparable to those in cortical neurons. 28 It is worth noting that FMRP is also expressed in spiral ganglion neurons, which convey acoustic signals from the inner ear to the brainstem, in both birds and mammals. In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels.…”

“…In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels. 28 In this section, we first describe the expression and function of FMRP in the ITD circuit (3.1) and then discuss how Fmr1 deletion affects the cell groups involved in ILD computation (3.2). Finally, we summarize effects of FMRP loss on auditory brainstem responses (ABRs), a noninvasive physiological output of the auditory brainstem (3.3).…”

Development of White Matter Circuitry in Infants With Fragile X Syndrome

“…This pattern of results suggests that loss of FMRP leads to variable outcomes on white matter circuitry, consistent with evidence that the protein is expressed differentially across brain regions and over time 39 and is pronounced in subcortical sensory and motor cells. 40 …”