LIPH Expression in Skin and Hair Follicles of Normal Coat and Rex Rabbits

Natural mutations in the LIPH gene were shown to be responsible for hair growth defects in humans and for the rex short hair phenotype in rabbits. In this species, we identified a single nucleotide deletion in LIPH (1362delA) introducing a stop codon in the C-terminal region of the protein. We investigated the expression of LIPH between normal coat and rex rabbits during critical fetal stages of hair follicle genesis, in adults and during hair follicle cycles. Transcripts were three times less expressed in both fetal and adult stages of the rex rabbits than in normal rabbits. In addition, the hair growth cycle phases affected the regulation of the transcription level in the normal and mutant phenotypes differently. LIPH mRNA and protein levels were higher in the outer root sheath (ORS) than in the inner root sheath (IRS), with a very weak signal in the IRS of rex rabbits. In vitro transfection shows that the mutant protein has a reduced lipase activity compared to the wild type form. Our results contribute to the characterization of the LIPH mode of action and confirm the crucial role of LIPH in hair production

Following the genes: a framework for animal modeling of psychiatric disorders

The number of individual cases of psychiatric disorders that can be ascribed to identified, rare, single mutations is increasing with great rapidity. Such mutations can be recapitulated in mice to generate animal models with direct etiological validity. Defining the underlying pathogenic mechanisms will require an experimental and theoretical framework to make the links from mutation to altered behavior in an animal or psychopathology in a human. Here, we discuss key elements of such a framework, including cell type-based phenotyping, developmental trajectories, linking circuit properties at micro and macro scales and definition of neurobiological phenotypes that are directly translatable to humans

The 16p11.2 locus modulates brain structures common to autism, schizophrenia and obesity

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy

Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders

Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain

Abnormalities of the axial and proximal appendicular skeleton in adults with Laron syndrome (growth hormone insensitivity)

To investigate abnormalities in the skeleton (with the exclusion of the skull, cervical spine, hands and feet) in patients with Laron syndrome, who have an inborn growth hormone resistance and congenital insulin-like growth factor-1 (IGF-1) deficiency. The study group was composed of 15 untreated patients with Laron syndrome (seven male and eight female) aged 21-68 years. Plain films of the axial and appendicular skeleton were evaluated retrospectively for abnormalities in structure and shape. The cortical width of the long bones was evaluated qualitatively and quantitatively (in the upper humerus and mid-femur), and the cortical index was calculated and compared with published references. Measurements were taken of the mid-anteroposterior and cranio-caudal diameters of the vertebral body and spinous process at L3, the interpedicular distance at L1 and L5, and the sacral slope. Thoracic and lumbar osteophytes were graded on a 5-point scale. Values were compared with a control group of 20 healthy persons matched for age. The skeleton appeared small in all patients. No signs of osteopenia were visible. The cortex of the long bones appeared thick in the upper limbs in 11 patients and in the lower limbs in four. Compared with the reference values, the cortical width was thicker than average in the humerus and thinner in the femur. The vertebral diameters at L3 and the interpedicular distances at L1 and L5 were significantly smaller in the patients than in the control subjects (P<0.001); however, at L5 the canal was wider, relative to the vertebral body. The study group had a higher rate of anterior osteophytes in the lumbar spine than the controls had, and their osteophytes were also significantly larger. In the six patients for whom radiographs of the upper extremity in its entirety were available on one film, the ulna appeared to be rotated. In one 22-year-old man, multiple epiphyses were still open. Congenital IGF-1 deficiency leads to skeletal abnormalities characterized by small bones, narrow spinal canal, and delayed bone age. The limitation in elbow distensibility common to patients with Laron syndrome may be related to a marked retroversion of the humeral head