Defects in tangential neuronal migration of pontine nuclei neurons in the Largemyd mouse are associated with stalled migration in the ventrolateral hindbrain.
The LARGE gene encodes a putative glycosyltransferase that is required for normal glycosylation of dystroglycan, and defects in LARGE can cause abnormal neuronal migration in congenital muscular dystrophy (CMD). Previous studies have focused on radial migration, which is disrupted at least in part due to breaks in the basal lamina. Through analysis of precerebellar nuclei development in the Large(myd) mouse hindbrain, we show that tangential migration of a subgroup of hindbrain neurons may also be disrupted. Within the precerebellar nuclei, the pontine nuclei (PN) are severely disrupted, whereas the inferior olive (IO), external cuneate nuclei (ECN) and lateral reticular nuclei (LRN) appear unaffected. Large and dystroglycan are widely expressed in the hindbrain, including in the pontine neurons migrating in the anterior extramural migratory stream (AES). BrdU labeling and immunohistochemical studies suggest normal numbers of neurons begin their journey towards the ventral midline in the AES in the Large(myd) mouse. However, migration stalls and PN neurons fail to reach the midline, surviving as ectopic clusters of cells located under the pial surface dorsally and laterally to where they normally would finish their migration near the ventral midline. Stalling of PN neurons at this location is also observed in other migration disorders in mice. These observations suggest that glycan-dependent dystroglycan interactions are required for PN neurons to correctly respond to signals at this important migrational checkpoint.
Qu
Qiang
Q
University of Massachusetts Medical School, Shriver Center, 200 Trapelo Road, Waltham, MA 02452, USA.
Crandall
James E
JE
Luo
Tuanlian
T
McCaffery
Peter J
PJ
Smith
Frances I
FI
D000596:Amino Acids; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D016695:Glycosyltransferases / Q000172:deficiency* / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007382:Intermediate Filaments / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012249:Rhombencephalon / Q000166:cytology* / Q000196:embryology / Q000254:growth & development
D000596:Amino Acids; D005136:Eye Proteins; D018398:Homeodomain Proteins; D007797:Laminin; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; C098463:dolaisoleucine; D049030:Dystroglycans; D016695:Glycosyltransferases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D001973:Bromodeoxyuridine