Hydrocephalus caused by conditional ablation of the Pten or beta-catenin gene

To investigate the roles of Pten and β-Catenin in the midbrain, either the Pten gene or the β-catenin gene was conditionally ablated, using Dmbx1 (diencephalon/mesencephalon-expressed brain homeobox gene 1)-Cre mice. Homozygous disruption of the Pten or β-catenin gene in Dmbx1-expressing cells caused severe hydrocephalus and mortality during the postnatal period. Conditional deletion of Pten resulted in enlargement of midbrain structures. β-catenin conditional mutant mice showed malformation of the superior and inferior colliculi and stenosis of the midbrain aqueduct. These results demonstrate that both Pten and β-Catenin are essential for proper midbrain development, and provide the direct evidence that mutations of both Pten and β-catenin lead to hydrocephalus

Neonatal Lethality, Dwarfism, and Abnormal Brain Development in Dmbx1 Mutant Mice

Dmbx1 encodes a paired-like homeodomain protein that is expressed in developing neural tissues during mouse embryogenesis. To elucidate the in vivo role of Dmbx1, we generated two Dmbx1 mutant alleles. Dmbx1(−) lacks the homeobox and Dmbx1(z) is an insertion of a lacZ reporter gene. Dmbx1(z) appears to be a faithful reporter of Dmbx1 expression during embryogenesis and after birth. Dmbx1-lacZ expression was detected in the superior colliculus, cerebellar nuclei, and subpopulations of the medulla oblongata and spinal cord. Some Dmbx1 homozygous mutant mice died during the neonatal period, while others survived to adulthood; however, their growth was impaired. Both heterozygous and homozygous mutant offspring from Dmbx1 homozygous mutant females exhibited a low survival rate and poor growth. However, even wild-type pups fostered onto Dmbx1 homozygous mutant females grew poorly, suggesting a Dmbx1-dependent nursing defect. Dmbx1 mutant mice had an aberrant Dmbx1-lacZ expression pattern in the nervous system, indicating that they had abnormal brain development. These results demonstrate that Dmbx1 is required for postnatal survival, growth, and brain development

Cloning and Functional Analysis of Hypothalamic Homeobox Gene Bsx1a and Its Isoform, Bsx1b▿

The hypothalamus is a key regulatory unit of the neuroendocrine system and plays an essential role in energy balance and reproduction. Despite its important role, the molecular mechanisms underlying hypothalamic development are not fully understood. Here, we report molecular analyses of a newly identified murine homeobox gene, Bsx/Bsx1a, that is expressed in the developing and postnatal hypothalamus. We demonstrate that BSX1A is a DNA binding protein and a transcriptional activator. Transcriptional reporter assays identified the C-terminal region of BSX1A as an activation domain. We have isolated an alternative splice form of Bsx1a, designated Bsx1b, which retains the N-terminal region but lacks the homeodomain. Analyses of subcellular localization using transfected cell lines revealed that BSX1A and BSX1B localize in the nuclei and cytoplasm, respectively. Immunohistochemical analyses suggested that both BSX1A and BSX1B are expressed in the neonatal hypothalamus. Taking these data together, we propose that alternative RNA splicing is involved in hypothalamic development/function

A Brain-Specific Homeobox Gene, Bsx, Is Essential for Proper Postnatal Growth and Nursing▿

To investigate in vivo roles of a murine hypothalamic homeobox gene, Bsx, we generated and analyzed two mutant alleles, BsxΔHD and BsxlacZ. BsxΔHD lacks the homeodomain, and BsxlacZ is an insertion of a lacZ reporter gene. Bsx-lacZ expression was detected in the hypothalamus and pineal gland and reiterates Bsx expression. Bsx homozygous mutant mice were born at the expected Mendelian ratio, but their growth was impaired. Offspring from Bsx homozygous mutant females exhibited a low survival rate due to a nursing defect. Mammary glands of the mutant females developed normally during pregnancy; however, they involuted quickly after parturition. These results demonstrate that Bsx is required for postnatal growth and maintenance of lactating mammary glands. Thus, mouse Bsx is likely involved in systemic control of suppression of apoptosis of postpartum mammary epithelial cells