The patterning of the vertebrate central nervous system is manifested as an organized production of specific neuronal subtypes with cell fate specification being part of this process. In this study, I focus on the role of an evolutionarily conserved gene, Mab21l2, in neural development. mab-21 was first identified in Caenorhabditis elegans as a cell fate specification gene in controlling male tail sensory ray development. Two vertebrate mab-21 homologs, Mab21l1 and Mab21l2, were reported to be highly expressed in partially overlapping domains in midbrain, eye, branchial arches, limb bud and spinal cord, while Mab21l2 was often expressed at a higher level than Mab21l1. Mab21l2 is essential for embryo survival as null mutant of Mab21l2 dies at mid-gestation stage. In this study, I g...[ Read more ]

The patterning of the vertebrate central nervous system is manifested as an organized production of specific neuronal subtypes with cell fate specification being part of this process. In this study, I focus on the role of an evolutionarily conserved gene, Mab21l2, in neural development. mab-21 was first identified in Caenorhabditis elegans as a cell fate specification gene in controlling male tail sensory ray development. Two vertebrate mab-21 homologs, Mab21l1 and Mab21l2, were reported to be highly expressed in partially overlapping domains in midbrain, eye, branchial arches, limb bud and spinal cord, while Mab21l2 was often expressed at a higher level than Mab21l1. Mab21l2 is essential for embryo survival as null mutant of Mab21l2 dies at mid-gestation stage. In this study, I generated neural progenitor cell-specific knock-out mice (Mab2l12^f/f;Nes-Cre) to investigate its role in neural development.

Mab21l2 is highly expressed in multiple subtypes of postmitotic spinal interneurons and various brainstem nuclei including those involved in respiration. Mab2l12^f/f;Nes-Cre mutants appear morphologically normal at all embryonic stages. Abnormality of cell fate specification or neuronal patterning was not detected in mutant spinal cord. At birth, Mab2l12^f/f;Nes-Cre mutants have a beating heart, but show no breathing movements. They turn cyanotic and die within minutes after birth due to respiratory failure. Postmortem lung examination never revealed dilated lung alveoli in mutant neonates despite a normal pattern of diaphragmatic innervation and neuromuscular formation. The lethal phenotype is possibly due to defect in the central control of respiration. Impaired development of NK1R/SST co-expressing preBötC neurons but not the RTN/pFRG neurons nor other respiratory motor nuclei in the medulla implies that Mab21l2 is critical for specifying the core rhythmogenic control, the deficit of which contributes to the respiratory failure of the homozygous neonates.