title: The transcription factor, Lmx1b, promotes a neuronal glutamate phenotype and suppresses a GABA one in the embryonic trigeminal brainstem complex.
abstract: Achieving an appropriate balance between inhibitory and excitatory neuronal fate is critical for development of effective synaptic transmission. However, the molecular mechanisms dictating such phenotypic outcomes are not well understood, especially in the whisker-to-barrel cortex neuraxis, an oft-used model system for revealing developmental mechanisms. In trigeminal nucleus principalis (PrV), the brainstem link in the whisker-barrel pathway, the transcription factor Lmx1b marks glutamatergic cells. In PrV of Lmx1b knockout mice (-/-), initial specification of glutamatergic vs. GABAergic cell fate is normal until embryonic day 14.5. Subsequently, until the day of birth, glutamatergic markers (e.g., VGLUT2) stain significantly fewer PrV neurons, whereas, GABAergic markers (Pax2 and Gad1) stain significantly more PrV cells, notably in Lmx1b null PrV cells. These changes also occurred in Lmx1b/Bax double-/- mice, where PrV cells are rescued from Lmx1b-/- induced apoptosis; thus, effects upon excitatory/inhibitory cell ratios do not reflect a cell death confound. Electroporation-induced ectopic expression of Lmx1b in an array of sites decreases numbers of neurons that express GABAergic markers, but increases VGLUT2+ cell numbers or stain intensity. Thus, Lmx1b is not involved in the initial specification of glutamatergic cell fate, but is essential for maintaining a glutamatergic phenotype. Other experiments suggest that Lmx1b acts to suppress Pax2, a promoter of GABAergic cell fate, in a cell-autonomous manner, which may be a mechanism for maintaining a functional balance of glutamatergic and GABAergic cell types in development.
authors.affiliation: Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine Pain Center, St Louis, MO 63110, USA.
authors.forename: Chuan-Xi
authors.initials: CX
authors.lastname: Xiang
authors.forename: Kai-Hua
authors.initials: KH
authors.lastname: Zhang
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.forename: Mark F
authors.initials: MF
authors.lastname: Jacquin
authors.forename: Zhou-Feng
authors.initials: ZF
authors.lastname: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D018274:Electroporation; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000145:classification / Q000378:metabolism*; D051762:PAX2 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*; D014278:Trigeminal Nuclei / Q000166:cytology* / Q000196:embryology; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C494827:Bax protein, mouse; C112149:LIM homeobox transcription factor 1 beta; D060850:LIM-Homeodomain Proteins; D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse; C493477:Slc17a6 protein, mouse; D014157:Transcription Factors; D050599:Vesicular Glutamate Transport Protein 2; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse; D051028:bcl-2-Associated X Protein; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1