Neutrophils are white blood cells that play critical roles in innate immunity. Upon activation by bacterial infections, neutrophils undergo a series of dynamic functional responses that include chemotaxis to sites of infection, phagocytosis of microbes and finally bacterial destruction. The unique multilobular structure of the neutrophil nucleus is characterized by multiple lobules that are connected by thin strands of heterochromatin. This structure has classically been viewed to increase nuclear fluidity, which aids the neutrophil to navigate between endothelial cells during the process of extravasation. Recent studies have demonstrated that mice homozygous for the ichthyosis mutation ( ic/ic) have neutrophils that resemble a severe form of human Pelger-Huët anomaly, a disorder that causes hypolobulation of blood neutrophils. The mutation disrupts the expression of the lamin B receptor (Lbr), a nuclear envelope protein that is essential for normal development of neutrophil nuclear structure. Our recent studies have confirmed that a model cell line, EPRO-ic/ic cells, accurately recapitulates the PHA found in ichthyosis mouse neutrophils. Furthermore, our studies demonstrated that the ic/ic neutrophils also display abnormal chemotaxis and growth responses, but normal phagocytosis. Here we describe further characterizations of these interesting cells by showing that chemotaxis responses are abnormal even at super-saturated levels, whereas wild-type cells show normal responses. However, we have shown that signaling downstream from the cytokine that stimulates EPRO-ic/ic cell growth is normal. Furthermore, the mutant cells also exhibit efficient killing of bacteria that is comparable to a heterozygous control line and wildtype cells. Our collective data indicate that loss of nuclear lobulation due to deficient Lbr expression impedes the capacity of neutrophils to migrate through a 3.0 μm space but most likely does not affect its capacity to bind to chemokines nor does it affect the capacity of neutrophils to kill bacteria. Macrophages are also professional phagocytes similar to neutrophils; both cell types derive from a common myeloid progenitor, and they both require common transcription factors for their differentiation, such as PU.1 and the CCAAT/enhancer binding proteins C/EBPa and C/EBPc. To further understand neutrophil vs. macrophage differentiation and possible roles for Lbr in each developmental pathway, we have also examined the development of two new models of neutrophil vs. macrophage differentiation, SCF ER-Hoxb8 and GM-CSF ER-Hoxb8 cells. Our studies reveal that both models demonstrate normal morphologic maturation, but differing functional responses as compared to the EPRO model system, including a lack of chemotaxis. We also identify unique changes in LBR gene expression during their differentiation that suggest that Lbr may play a role in both developmental pathways, but levels of expression are unique between these two professional phagocytes. Together, our results add to an impressive body of data that demonstrates roles for Lbr in the development of multiple myeloid cell pathways, and that multiple regulators act to drive Lbr expression in these pathways.