title: Neuronal defects in the hindbrain of Hoxa1, Hoxb1 and Hoxb2 mutants reflect regulatory interactions among these Hox genes.
abstract: Hox genes are instrumental in assigning segmental identity in the developing hindbrain. Auto-, cross- and para-regulatory interactions help establish and maintain their expression. To understand to what extent such regulatory interactions shape neuronal patterning in the hindbrain, we analysed neurogenesis, neuronal differentiation and motoneuron migration in Hoxa1, Hoxb1 and Hoxb2 mutant mice. This comparison revealed that neurogenesis and differentiation of specific neuronal subpopulations in r4 was impaired in a similar fashion in all three mutants, but with different degrees of severity. In the Hoxb1 mutants, neurons derived from the presumptive r4 territory were re-specified towards an r2-like identity. Motoneurons derived from that territory resembled trigeminal motoneurons in both their migration patterns and the expression of molecular markers. Both migrating motoneurons and the resident territory underwent changes consistent with a switch from an r4 to r2 identity. Abnormally migrating motoneurons initially formed ectopic nuclei that were subsequently cleared. Their survival could be prolonged through the introduction of a block in the apoptotic pathway. The Hoxa1 mutant phenotype is consistent with a partial misspecification of the presumptive r4 territory that results from partial Hoxb1 activation. The Hoxb2 mutant phenotype is a hypomorph of the Hoxb1 mutant phenotype, consistent with the overlapping roles of these genes in facial motoneuron specification. Therefore, we have delineated the functional requirements in hindbrain neuronal patterning that follow the establishment of the genetic regulatory hierarchy between Hoxa1, Hoxb1 and Hoxb2.
authors.affiliation: Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gavalas
authors.forename: Christiana
authors.initials: C
authors.lastname: Ruhrberg
authors.forename: Jean
authors.initials: J
authors.lastname: Livet
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Henderson
authors.forename: Robb
authors.initials: R
authors.lastname: Krumlauf
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D019521:Body Patterning; D002454:Cell Differentiation; D002465:Cell Movement / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D050989:GATA2 Transcription Factor; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012249:Rhombencephalon / Q000002:abnormalities / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D051028:bcl-2-Associated X Protein; D000099261:Homeobox A1 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051028:bcl-2-Associated X Protein; D000099261:Homeobox A1 Protein; C494712:Gata2 protein, mouse; C101121:HOXB1 homeodomain protein; C490111:Hoxb2 protein, mouse; C109220:NBPhox protein; C104516:Neurod4 protein, mouse