The long-standing doctrine regarding the functional organization of the direct dorsal column (DDC) pathway is the "somatotopic map" model, which suggests that somatosensory afferents are primarily organized by receptive field instead of modality. Using modalityspecific genetic tracing, here we show that ascending mechanosensory and proprioceptive axons, two main types of the DDC afferents, are largely segregated into a medial-lateral pattern in the mouse dorsal column and medulla. In addition, we found that this modality-based organization is likely to be conserved in other mammalian species, including human. Furthermore, we identified key morphological differences between these two types of afferents, which explains how modality segregation is formed and why a rough "somatotopic map" was previously detected. Collectively, our results establish a new functional organization model for the mammalian direct dorsal column pathway and provide insight into how somatotopic and modality-based organization coexist in the central somatosensory pathway.

Fatty acid 2-hydroxylase (FA2H) is responsible for the synthesis of myelin galactolipids containing hydroxy fatty acid (hFA) as the N-acyl chain. Mutations in the FA2H gene cause leukodystrophy, spastic paraplegia, and neurodegeneration with brain iron accumulation. Using the Cre-lox system, we developed two types of mouse mutants, Fa2h−/− mice (Fa2h deleted in all cells by germline deletion) and Fa2hflox/flox Cnp1-Cre mice (Fa2h deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of Fa2h−/− mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected. Fa2h−/− mice also exhibited histological and functional disruption in the cerebellum at 12 months of age. In a time course study, significant deterioration of cerebellar function was first detected at 7 months of age. Further behavioral assessments in water T-maze and Morris water maze tasks revealed significant deficits in spatial learning and memory at 4 months of age. These data suggest that various regions of the CNS are functionally compromised in young adult Fa2h−/− mice. The cerebellar deficits in 12-month-old Fa2hflox/flox Cnp1-Cre mice were indistinguishable from Fa2h−/−mice, indicating that these phenotypes likely stem from the lack of myelin hFA-galactolipids. In contrast, Fa2hflox/flox Cnp1-Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in Fa2h−/− mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS.

No abstract

Mutations in TUBB4A result in a spectrum of leukodystrophy including Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC), a rare hypomyelinating leukodystrophy, often associated with a recurring variant p.Asp249Asn (D249N). We have developed a novel knock-in mouse model harboring heterozygous (Tubb4aD249N/+) and the homozygous (Tubb4aD249N/D249N) mutation that recapitulate the progressive motor dysfunction with tremor, dystonia and ataxia seen in H-ABC. Tubb4aD249N/D249N mice have myelination deficits along with dramatic decrease in mature oligodendrocytes and their progenitor cells. Additionally, a significant loss occurs in the cerebellar granular neurons and striatal neurons in Tubb4aD249N/D249N mice. In vitro studies show decreased survival and dysfunction in microtubule dynamics in neurons from Tubb4aD249N/D249N mice. Thus Tubb4aD249N/D249N mice demonstrate the complex cellular physiology of H-ABC, likely due to independent effects on oligodendrocytes, striatal neurons, and cerebellar granule cells in the context of altered microtubule dynamics, with profound neurodevelopmental deficits.

Key pointsr The G-protein-mediated metabotropic glutamate receptor 6 (mGluR6) signalling cascade is critical for light responses in all retinal ON bipolar cells. The present study evaluates the role of G-protein subunit Gγ13 in ON bipolar cells by deleting the mouse Gng13 gene.r Gγ13 is a partner of Gβ3 in all types of retinal ON bipolar cells, and contributes to generating the light response.r Gγ13 also contributes to maintenance because, in its absence, the light response decreases with age.r Three independent functionality assessments (i.e. light response as measured by electroretinogram b-waves, localization of GTPase activating proteins and deterioration of the light response with age) show that the contribution of Gγ13 is much greater in rod bipolar cells than in ON cone bipolar cells.r Our data also suggest that the contribution of Gγ13 to coupling mGluR6 to its effector is smaller than its contribution to maintaining GTPase activating protein localization.Abstract Heterotrimeric G-proteins (comprising Gα and Gβγ subunits) are critical for coupling of metabotropic receptors to their downstream effectors. In the retina, glutamate released from photoreceptors in the dark activates metabotropic glutamate receptor 6 (mGluR6) receptors in ON bipolar cells; this leads to activation of G o , closure of transient receptor potential melastatin 1 channels and hyperpolarization of these cells. G o comprises Gα o , Gβ3 and a Gγ. The best Gγ candidate is Gγ13, although functional data to support this are lacking. Thus, we tested Gγ13 function by generating Gng13 −/− knockout (KO) mice, recording electroretinograms (ERG) and performing immunocytochemical staining. The amplitude of scotopic ERG b-waves in KO mice was lower than in wild-type (WT) mice. Furthermore, in both KO and WT mice, the ERG b-wave decreased with age; this decrease was much more pronounced in KO mice. By contrast, the photopic ERG b-waves in KO mice were hardly affected at any age. In KO mice retinas, immunostaining for Gβ3 and for the GTPase activating proteins RGS7, RGS11, R9AP and Gβ5 decreased significantly in rod bipolar cells but not in ON cone bipolar cells. Staining for Gα o and certain other cascade elements decreased only slightly. Analysis of our ON bipolar cDNA library showed that these cells express mRNAs for Gγ5, Gγ10 and Gγ11. Quantitative RT-PCR of retinal cDNA showed greater values for these transcripts in retinas of KO mice, although the difference was not significant. Our results suggest that Gγ13 contributes to mGluR6 signalling in rod bipolar cells more than in ON cone bipolar cells, and that this contribution includes both coupling the receptor and maintaining a stable localization of the mGluR6-related cascade elements.