| Description |
Hox proteins are homeodomain containing, sequence specific, DNA-binding transcription factors that play a crucial role in the specification of antero-posterior identity in the animal. Loss of function analysis, through targeted gene inactivation, has provided valuable insight as to where individual Hox genes are acting to specify cell fates along the axis of the developing mouse embryo. It has been demonstrated that mutations in 3' genes directly affect the development of anterior embryonic structures, whereas inactivation of 5' genes results in abnormal development of posterior structures. Mouse models generated with mutations in the 3' paralogs result in cranio-facial defects and loss of various neuronal populations along the head and neck region, phenotypes typical of deficiencies in neural crest and/or hindbrain derivatives. Hoxb1 is one such 3' paralog. Targeted inactivation of the Hoxb1 gene has provided an ideal model for studying the molecular mechanisms associated with neuronal specification, maturation, and/or survival. Homozygous mutant mice harboring null alleles of Hoxb1 fail to form the facial branchio-motor components of the VII cranial nerve, a specific population of neurons born in the fourth rhombomeric segment (r4) of the hindbrain that are destined to innervate target tissues of the second branchial arch. In wildtype animals, Hoxb1 is regionally restricted in expression and function to the neural tube and migrating neural crest cells within r4 of the mouse hindbrain, implicating two populations of cells that may contribute to the normal development of the VIIth cranial nerve circuitry. To date, analysis of this phenotype has focused predominantly on the progenitor pools within the neural tube that become the VIIth nerve motoneurons and has included the characterization of anatomical and molecular differences between mutant and wildtype cells. The focus of this thesis has been to address the novel, pleiotropic roles for Hoxb1 in the formation and maintenance of the VIIth cranial nerve circuitry by uncoupling the different functions for Hoxb1 in motoneuron specification within the CNS and the neural crest cell programming in the periphery. |
