Oculodentodigital dysplasia (ODDD) is an autosomal dominant disorder characterized by pleiotropic developmental anomalies of the limbs, teeth, face and eyes that was shown recently to be caused by mutations in the gap junction protein alpha 1 gene (GJA1), encoding connexin 43 (Cx43). In the course of performing an N-ethyl-N-nitrosourea mutagenesis screen, we identified a dominant mouse mutation that exhibits many classic symptoms of ODDD, including syndactyly, enamel hypoplasia, craniofacial anomalies and cardiac dysfunction. Positional cloning revealed that these mice carry a point mutation in Gja1 leading to the substitution of a highly conserved amino acid (G60S) in Cx43. In vivo and in vitro studies revealed that the mutant Cx43 protein acts in a dominant-negative fashion to disrupt gap junction assembly and function. In addition to the classic features of ODDD, these mutant mice also showed decreased bone mass and mechanical strength, as well as altered hematopoietic stem cell and progenitor populations. Thus, these mice represent an experimental model with which to explore the clinical manifestations of ODDD and to evaluate potential intervention strategies.

ChAT-ty T cells fight viral infection: The neurotransmitter acetylcholine (ACh) is involved in processes such as muscle contraction, neuron communication, and vasodilation. Along with neurons, a population of immunological T cells and B cells express the enzyme choline acetyltransferase (ChAT), which catalyzes the rate-limiting step of ACh production. However, the role of immune cell–derived ACh is unclear. Cox et al. report that the cytokine interleukin-21 (IL-21) induces ChAT expression in CD4 ⁺ and CD8 ⁺ T cells during lymphocytic choriomeningitis virus infection (see the Perspective by Hickman). T cell–specific deletion of ChAT strongly impaired vasodilation and trafficking of antiviral T cells into infected tissues, which undermined the effective control of a chronic viral infection. Thus, IL-21 plays a critical role during chronic infection. Furthermore, the findings reveal a cholinergic mechanism that can regulate immune cell migration into tissues. Science , this issue p. 639 ; see also p. 585

Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI’s ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.

High-frequency ultrasound biomicroscopy (UBM) has recently emerged as a high-resolution means of phenotyping genetically altered mice and has great potential to evaluate the cardiac morphology and hemodynamics of mouse mutants. However, there is no standard procedure of in vivo transthoracic cardiac imaging using UBM to comprehensively phenotype the adult mice. In this paper, the characteristic mouse thoracic anatomy is elucidated using magnetic resonance (MR) imaging on fixed mice. Besides the left parasternal and apical windows commonly used for transthoracic ultrasound cardiac imaging, a very useful right parasternal window is found. We present strategies for optimal visualization using UBM of key cardiac structures including: 1 ) the right atrial inflow channels such as the right superior vena cava; 2 ) the right ventricular inflow tract via the tricuspid orifice; 3 ) the right ventricular outflow tract to the main pulmonary artery; 4 ) the left atrial inflow channel, e.g., pulmonary vein; 5 ) the left ventricular inflow tract via the mitral orifice; 6 ) the left ventricular outflow tract to the ascending aorta; 7 ) the left coronary artery; and 8 ) the aortic arch and associated branches. Two-dimensional ultrasound images of these cardiac regions are correlated to similar sections in the three-dimensional MR data set to verify anatomical details of the in vivo UBM imaging. Dimensions of the left ventricle and ascending aorta are measured by M-mode. Flow velocities are recorded using Doppler at six representative intracardiac locations: right superior vena cava, tricuspid orifice, main pulmonary artery, pulmonary vein, mitral orifice, and ascending aorta. The methodologies and baseline measurements of inbred mice provide a useful guide for investigators applying the high-frequency ultrasound imaging to mouse cardiac phenotyping.

Since genetically modified mice have become more common in biomedical research as models of human disease, a need has also grown for efficient and quantitative methods to assess mouse phenotype. One powerful means of phenotyping is characterization of anatomy in mutant vs. normal populations. Anatomical phenotyping requires visualization of structures in situ, quantification of complex shape differences between mouse populations, and detection of subtle or diffuse abnormalities during high-throughput survey work. These aims can be achieved with imaging techniques adapted from clinical radiology, such as magnetic resonance imaging and computed tomography. These imaging technologies provide an excellent nondestructive method for visualization of anatomy in live individuals or specimens. The computer-based analysis of these images then allows thorough anatomical characterizations. We present an automated method for analyzing multiple-image data sets. This method uses image registration to identify corresponding anatomy between control and mutant groups. Within- and between-group shape differences are used to map regions of significantly differing anatomy. These regions are highlighted and represented quantitatively by displacements and volume changes. This methodology is demonstrated for a partially characterized mouse mutation generated by N-ethyl-N-nitrosourea mutagenesis that is a putative model of the human syndrome oculodentodigital dysplasia, caused by point mutations in the gene encoding connexin 43.