Family Member L1 Research Articles

Distribution of glial cells in the auditory brainstem: Normal development and effects of unilateral lesion

Auditory brainstem networks facilitate sound source localization through binaural integration. A key component of this circuitry is the projection from the ventral cochlear nucleus (VCN) to the medial nucleus of the trapezoid body (MNTB), a relay nucleus that provides inhibition to the superior olivary complex. This strictly contralateral projection terminates in the large calyx of Held synapse. The formation of this pathway requires spatiotemporal coordination of cues that promote cell maturation, axon growth, and synaptogenesis. Here we have examined the emergence of distinct classes of glial cells, which are known to function in development and in response to injury. Immunofluorescence for several astrocyte markers revealed unique expression patterns. Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) was expressed earliest in both nuclei, followed by S100ß, during the first postnatal week. Glial fibrillary acidic protein (GFAP) expression was seen in the second postnatal week. GFAP-positive cell bodies remained outside the boundaries of VCN and MNTB, with a limited number of labeled fibers penetrating into the margins of the nuclei. Oligodendrocyte transcription factor 2 (OLIG2) expression revealed the presence of oligodendrocytes in VCN and MNTB from birth until after hearing onset. In addition, ionized calcium binding adaptor molecule 1 (IBA1)-positive microglia were observed after the first postnatal week. Following hearing onset, all glial populations were found in MNTB. We then determined the distribution of glial cells following early (P2) unilateral cochlear removal, which results in formation of ectopic projections from the intact VCN to ipsilateral MNTB. We found that following perturbation, astrocytic markers showed expression near the ectopic ipsilateral calyx. Taken together, the developmental expression patterns are consistent with a role for glial cells in the maturation of the calyx of Held and suggest that these cells may have a similar role in maturation of lesion-induced connections.

The astrocyte marker Aldh1L1 does not reliably label enteric glial cells

Enteric glial cells are increasingly acknowledged as important partners of enteric neurons in the control of gastrointestinal function. They share morphological features and expression of antigenic markers with astrocytes of the central nervous system. Recently, aldehyde dehydrogenase 1 family member L1 (Aldh1L1) has been proposed as a novel and specific marker for astrocytes. Taking the known similarities between astrocytes and enteric glia into account, we sought to investigate whether enteric glial cells also express Aldh1L1. To this end, we performed immunostaining on preparations of myenteric plexus obtained from adult Aldh1L1-eGFP bacterial artificial chromosome (BAC) transgenic mice and found that the Aldh1L1 promoter is indeed active in enteric glia, albeit mainly in cells residing outside the myenteric ganglia. Apart from enteric glia, we also observed eGFP expression in interstitial cells of Cajal. Furthermore, myenteric ganglia of the large intestine contained eGFP positive neurons. Taken together, our data indicate that Aldh1L1 is not a suitable marker for enteric glial cells.

Decreased expression of ALDH1L1 is associated with a poor prognosis in hepatocellular carcinoma

Microarray data suggested that the expression of aldehyde dehydrogenase 1 family member L1 (ALDH1L1) is reduced in hepatocellular carcinoma (HCC). However, the role of ALDH1L1 in HCC carcinogenesis has not been elucidated. In the present study, we investigated the expression of ALDH1L1 in HCC and evaluated its relationship with clinical features and prognosis of HCC patients. Total 112 tumor samples were collected from patients with HCC, who underwent radical hepatectomy. Out of the 112 samples, 16 paired HCC tumorous and corresponding adjacent nontumor tissues were analyzed by real-time quantitative RT-PCR (qRT-PCR) and Western blotting, and the other 96 HCC samples were detected by immunohistochemical method. The qRT-PCR assay showed that the mRNA level of ALDH1L1 was significantly reduced in tumorous tissues compared with the adjacent nontumorous tissues (P = 0.0007), and Western blotting indicated that protein level of ALDH1L1 also notably down-regulated in tumor tissues. Immunohistochemistry detection revealed that decreased ALDH1L1 expression was present in 56.3% (54/96) of HCC patients. Correlation analysis showed that ALDH1L1 expression was significantly correlated with histological differentiation (P = 0.001), HBsAg status (P = 0.024) and serum AFP (P = 0.001). Patients with low expression of ALDH1L1 had poorer prognosis than those with high expression (P = 0.008). Multivariate analysis showed that ALDH1L1 expression was an independent predictor of overall survival (HR, 0.349; 95% CI, 0.157-0.774; P = 0.01). The results in this study, for the first time, reveal that the mRNA and protein expressions of ALDH1L1 are significantly reduced in HCC tissues and its low protein expression is a new and potential prognostic marker for the survival of HCC patients.

Astrocyte and Glutamate Markers in the Superficial, Deep, and White Matter Layers of the Anterior Cingulate Gyrus in Schizophrenia

Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors. Recent evidence suggests that it is no longer tenable to consider neurons and their functions independently of the glia that interact with them. Although astrocytes have been viewed as harbingers of neuronal injury and CNS stress, their principal functions include maintenance of glutamate homeostasis and recycling, mediation of saltatory conduction, and even direct neurotransmission. Results of studies of astrocytes in schizophrenia have been variable, in part because of the assessment of single and not necessarily universal markers and/or assessment of non-discrete brain regions. We used laser capture microdissection to study three distinct partitions of the anterior cingulate gyrus (layers I-III, IV-VI, and the underlying white matter) in the brains of 18 well-characterized persons with schizophrenia and 21 unaffected comparison controls. We studied the mRNA expression of nine specific markers known to be localized to astrocytes. The expression of astrocyte markers was not altered in the superficial layers or the underlying white matter of the cingulate cortex of persons with schizophrenia. However, the expression of some astrocyte markers (diodinase type II, aquaporin-4, S100β, glutaminase, excitatory amino-acid transporter 2, and thrombospondin), but not of others (aldehyde dehydrogenase 1 family member L1, glial fibrillary acidic protein, and vimentin) was significantly reduced in the deep layers of the anterior cingulate gyrus. These findings suggest that a subset of astrocytes localized to specific cortical layers is adversely affected in schizophrenia and raise the possibility of glutamatergic dyshomeostasis in selected neuronal populations.

Gene expression profiling of NF-1-associated and sporadic pilocytic astrocytoma identifies aldehyde dehydrogenase 1 family member L1 (ALDH1L1) as an underexpressed candidate biomarker in aggressive subtypes.

Pilocytic astrocytomas (PAs) are World Health Organization Grade I gliomas; they most often affect children and young adults and occur in patients with neurofibromatosis type 1 (NF1). To identify genes that are differentially expressed in sporadic (S-PA) versus NF1-associated PAs (NF1-PAs) and those that might reflect differences in clinical behavior, we performed gene expression profiling using Affymetrix U133 Plus2.0 GeneChip arrays in 36 S-PAs and 11 NF1-PAs. Thirteen genes were overexpressed, and another 13 genes were underexpressed in NF1-PAs relative to S-PAs. Immunohistochemical studies performed on 103 tumors, representing 2 independently generated tissue microarrays, confirmed the differential expression of CUGBP2 (p = 0.0014), RANBP9 (p = 0.0075), ITGAV1 (p = 0.0001), and INFGR1 (p = 0.024) proteins. One of the underexpressed genes, aldehyde dehydrogenase 1 family member L1 (ALDH1L1), was also reduced in clinically aggressive compared with typical PAs (p = 0.01) and in PAs with increased cellularity and necrosis. Furthermore, in an additional independent set of tumors, weak to absent ALDH1L1 expression was found in 13 (72%) of 18 clinically aggressive PAs, in 8 (89%) of 9 PAs with pilomyxoid features, in 7 (70%) of 10 PAs with anaplastic transformation, and in 16 (76%) of 21 diffusely infiltrating astrocytomas of various grades. In summary, we have identified a molecular signature that distinguishes NF1-PA from S-PA and found that ALDH1L1 underexpression is associated with aggressive histology and/or biologic behavior.

Second-trimester exposure to maternal stress is a possible risk factor for psychotic illness in the child

Patients with schizophrenia (SCZ) run a lifelong risk of suicide. Alterations in glia activities in the prefrontal cortex (PFC) have been reported in relation to suicide in patients with SCZ. While immune processes in the CNS have been related to the susceptibility and course of SCZ, there are hardly any direct comparisons between individuals with SCZ, both those who died of natural causes and those that committed suicide, and healthy controls.We compared mRNA expression using real time qPCR of 16 glia-related genes in the dorsal lateral prefrontal cortex (DLPFC) and the anterior cingulate cortex (ACC) between 35 patients with SCZ (7 suicide completers and 28 patients who died of natural causes) and 34 well-matched controls without psychiatric or neurological diseases.We found an increased expression of the astrocytic gene aldehyde dehydrogenase-1 family member L1 (ALDH1L1) mRNA, a marker involved in dopaminergic activity, in SCZ versus controls. Excluding individuals with SCZ that committed suicide resulted in an elevated expression in the DLPFC of both ALDH1L1 and glutamine synthetase (GS) genes in patients with SCZ, compared to suicide completers and non-psychiatric controls. Regarding microglia genes: in the ACC, homeostatic markers such as chemokine (C-X3-C motif) ligand 1 (CX3CR1) mRNA expression was increased in SCZ without suicide as compared to suicide completers, while no change was found when compared to controls. Another, purinergic receptor 12 (P2RY12) mRNA was exclusively elevated in the ACC of suicide completers, compared to either other group. Triggering receptor expressed on myeloid cells 2 (TREM2) expression, which maintains microglial metabolism, was reduced in non-suicide patients with SCZ, compared to suicide victims and control subjects.Differential changes are found in astrocyte and microglia genes in the PFC subregions in relation to SCZ and suicide, indicating possible disturbances of glia homeostasis in these conditions.