Thus the phenotype of a-casein deficient dams and their offspring confirm the critical role of lactation in determining lifelong body size and underline the decisive role of protein supply during this developmental window. These mice represent a genetically defined model system of nutritional restriction with a significant impact on whole animal metabolism. This model can be exploited to study mechanistic aspects of metabolic programming of body size, resistance to obesity and long-term health outcomes. Geometry and Adhesion of Extracellular Domains of DC-SIGNR Neck Length Variants Analyzed by Force–Distance Measurements [Image: see text] Force–distance measurements have been used to examine differences in the interaction of the dendritic cell glycan-binding receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR (L-SIGN) with membranes bearing glycan ligands. The results demonstrate that upon binding to membrane-anchored ligand, DC-SIGNR undergoes a conformational change similar to that previously observed for DC-SIGN. The results also validate a model for the extracellular domain of DC-SIGNR derived from crystallographic studies. Force measurements were performed with DC-SIGNR variants that differ in the length of the neck that result from genetic polymorphisms, which encode different numbers of the 23-amino acid repeat sequences that constitute the neck. The findings are consistent with an elongated, relatively rigid structure of the neck repeat observed in crystals. In addition, differences in the lengths of DC-SIGN and DC-SIGNR extracellular domains with equivalent numbers of neck repeats support a model in which the different dispositions of the carbohydrate-recognition domains in DC-SIGN and DC-SIGNR result from variations in the sequences of the necks. T he human glycan-binding receptors DC-SIGN (dendriticcell-specific intercellular adhesion molecule 1-grabbing nonintegrin; CD209) and DC-SIGNR (DC-SIGN-related receptor, also designated as L-SIGN, CD209L, and CD299) share overall sequence identity of 77% and arose by a relatively recent gene duplication within the primate lineage. DC-SIGN is expressed on dendritic cells and some macrophages, while DC-SIGNR is expressed on endothelial cells in the liver and lymph node sinusoids and in cells lining placental capillaries. 1À3 Expression of these receptors on distinct cell types suggests that they have potentially different functions. Both bind to the T-cell surface receptor ICAM-3 1,2 in order to facilitate infection of T cells by human immunodeficiency virus (HIV 4 ) and act as primary receptors that mediate entry of Ebola virus into cells. 4, 5 However, they bind differentially to other pathogens. 6 For example, DC-SIGN plays a critical role in modulating the host response to schistosomal parasites, and it interacts with Helicobacter pylori, while DC-SIGNR facilitates infection of hepatocytes, by presenting hepatitis C virus on liver endothelial cells. 7 DC-SIGNR also promotes transmission of human immunodeficiency virus across the placenta. 8 These differences in the biological properties of DC-SIGN and DC-SIGNR are mirrored by differences in their molecular properties. For example, although both receptors bind to highmannose oligosaccharides, these are the only glycans that are detected in glycan array analysis of DC-SIGNR, while the presence of key residues in the carbohydrate-recognition domain (CRD) of DC-SIGN, particularly Val351, supports binding to fucosylated Lewis-type oligosaccharide structures as well. 9 Such differences probably explain why DC-SIGN binds to parasites that are rich in such structures, while DC-SIGNR does not. 10, 11 In addition to these differences in the ligand-binding domains of DC-SIGN and DC-SIGNR, there appear to be significant but less well understood differences in their overall architectures ( Figure 1A ,B). In both receptors, the carbohydrate-recognition domains are projected from the cell surface by a neck domain comprising multiple copies of a 23-amino acid repeat sequence, but the number of copies of the repeat is largely fixed fixed at 7.5 in DC-SIGN, while polymorphisms in the gene for DC-SIGNR result in variant forms of the neck containing between 4.5 and 9.5 repeats. 12, 13 The allele frequency of the 7.5-repeat variant is over 50% in the human population, but the frequencies of the 6.5and 5.5-repeat variants are 12À16% and 26À37%, respectively. Different neck-length genotypes have been associated with variations in susceptibility to certain viral infections. The 7.5-repeat form is more common in HIV-infected individuals than in uninfected individuals. 14 However, this correlation with HIV susceptibility has not been observed in all cases. 12 The presence of 4.5repeat and 9.5-repeat variants correlates with decreased viral load in hepatitis C virus infection. 15 The shorter necks are also associated with diminished rates of SARS coronavirus infection. 16 It is also noteworthy that the neck repeat adjacent to the CRD of DC-SIGNR differs significantly in sequence from the Biochemistry ARTICLE corresponding sequence in DC-SIGN. Recent structural analysis of a truncated form of the neck domain of DC-SIGNR, combined with a structure of the final neck repeat attached to the CRD, has indicated that a phenylalanine in the final neck repeat of DC-SIGNR causes the polypeptides forming the necks to splay apart at this point. 17 In DC-SIGN, the presence of a valine residue at this position suggests that the neck could remain packed as they are in the other neck repeats, thereby placing the CRDs closer to each other. Thus, differences in the neck regions of DC-SIGN and DC-SIGNR may also contribute to differences in their interactions with pathogens.