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doi: 10.1242/10.1242/jcs.00169

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Absence of retinoids can induce motoneuron disease in the adult rat and a retinoid defect is present in motoneuron disease patients

Jonathan Corcoran^*,, Po Lin So and Malcolm Maden

MRC Centre for Developmental Neurobiology, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK
^* Present address: Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK

View larger version (10K): [in a new window]   Fig. 1. HPLC analysis of blood of rats. (A) 1-year-old normally fed rats; (B) 1-year-old retinoid-deficient rats. Arrows indicate retinol peak. The amount of retinol in the normally fed rat is 665 ng/ml blood; in the retinoid-deficient rat no retinol could be detected. Similar data were obtained from four other control rats and seven retinoid-deficient rats.

View larger version (70K): [in a new window]   Fig. 2. Effect of a retinoid-deficient diet on adult rats. (A) 6-month-old normally fed rat; (B) 6-month-old retinoid-deficient rat. Normal rats (A) extend their hindlimbs when they are held by the tail, whereas retinoid-deficient rats retract their hindlimbs. n=5-8.

View larger version (132K): [in a new window]   Fig. 3. Expression of NF200 in lumbar (A,B) and cervical cord (C,D). (A) Lumbar cord of a 6-month-old normally fed rat. (B) Lumbar cord of a 6-month-old retinoid-deficient rat. (C) Cervical cord of a 6-month-old normally fed rat. (D) Cervical cord of 6-month-old retinoid-deficient rat. Black arrows and arrowheads indicate motoneurons. The arrowheads indicate motoneurons with vacuolar lesions. The white arrow indicates accumulation of neurofilament in the axons. Similar data were obtained from four other normal fed rats and seven other retinoid-deficient rats.

View larger version (14K): [in a new window]   Fig. 4. A graph showing the percentage loss of motoneurons in the lumbar cord of the retinoid-deficient rats compared with the normally fed rats. Columns: 1, normally fed rats; 2, retinoid-deficient rats; 3, motoneurons with vacuolations in the retinoid-deficient rat. Error bar=s.e.m. There was a significant difference between the percentage of motoneurons in the normal and retinoid-deficient rats of *P<0.01. Students t-test, n=5-8.

View larger version (42K): [in a new window]   Fig. 5. Reactive astrocytosis in the lumbar cord of 6-month-old rats. Expression of GFAP in astrocytes. (A) Normal lumbar cord; (B) retinoid-deficient lumbar cord; (C) western blot of lumbar cord of 6-month-old rats, lanes: 1, normal lumbar cord lane 2, retinoid-deficient lumbar cord. The arrow indicates a protein band of the correct size. Similar data were obtained from four other normally fed rats and seven other retinoid-deficient rats.

View larger version (74K): [in a new window]   Fig. 6. Expression of RAR and raldh-2 in motoneurons of lumbar cord of the of 6-month-old adult rat. In situ hybridization of A, RAR expression in motoneurons of normal fed rat; B, RAR expression in motoneurons of retinoid deficient rat; C, raldh-2 expression in motoneurons of normal fed rat; D, raldh-2 expression in motoneurons of retinoid deficient rat; E, quantification of the in situ signals of RAR (columns 1 and 2) and raldh-2 (columns 3 and 4) expression compared with gapdh in motoneurons. Columns: 1 and 3, normally fed rats; 2 and 4, retinoid-deficient rats. Error bar=s.e.m. There was a significant difference in RAR expression *P<0.01 but not raldh-2 expression between normally fed and retinoid-deficient rats. Students t-test, n=5-8. Arrows indicate motoneurons.

View larger version (175K): [in a new window]   Fig. 7. Expression of islet-1 and components of the retinoid signalling pathway by in situ hybridisation in the lumbar cord of a normal (A,C,E) and an aged-matched patient suffering from spontaneous motoneuron disease (B,D,F). A,B, islet-1 expression; C,D, RAR expression; E,F, raldh-2 expression. Arrows indicate motoneurons. The brown deposit is lipofuscin, which is expressed by aged neurons. This does not interfere with the quantitative analysis. The same data was obtained from nine other patients.

View larger version (21K): [in a new window]   Fig. 8. Graph showing the percentage of motoneurons in the lumbar cord expressing islet-1 and components of the retinoid signalling pathway in aged-matched normal and motoneuron disease patients. Columns: 1, islet-1-positive motoneurons in normal cord; 2, islet-1-positive motoneurons in diseased cord; 3, RAR-positive motoneurons in normal cord; 4. RAR-positive motoneurons in diseased cord; 5, raldh-2-positive motoneurons in normal cord; 6, raldh-2-positive motoneurons in diseased cord. Error bar=s.e.m. There was no significant difference between the percentage of islet-1 motoneurons in normal and diseased aged-matched samples (columns 1 and 2). There was a significant difference between the number of RAR-positive motoneurons (columns 3 and 4) *P<0.01 and between the number of raldh-2-positive motoneurons (columns 5 and 6) **P<0.001 of normal and diseased aged-matched samples. Students t-test, n=10.

View larger version (21K): [in a new window]   Fig. 9. Quantification of in situ hybridisation of islet-1 and components of the retinoid signalling pathway in the motoneurons in aged-matched normal and motoneuron disease patients compared to gapdh. Columns: 1, islet-1 expression in motoneurons of normal cord; 2, islet-1 expression in motoneurons of diseased cord; 3, RAR expression in motoneurons of normal cord; 4, RAR expression in motoneurons of diseased cord; 5, raldh-2 expression in motoneurons of normal cord; 6, raldh-2 expression in motoneurons of diseased cord. Error bar=s.e.m. There was a significant difference between islet-1 expression (columns 1 and 2), RAR expression (columns 3 and 4) and between raldh-2 expression (columns 5 and 6) *P<0.05 of normal and diseased aged matched samples. Students t-test, n=10.