SUMMARYProgenitor cells in the cerebral cortex undergo dynamic cellular and molecular changes during development. Sall1 is a putative transcription factor that is highly expressed in progenitor cells during development. In humans, the autosomal dominant developmental disorder Townes-Brocks syndrome (TBS) is associated with mutations of the SALL1 gene. TBS is characterized by renal, anal, limb and auditory abnormalities. Although neural deficits have not been recognized as a diagnostic characteristic of the disease, ∼10% of patients exhibit neural or behavioral abnormalities. We demonstrate that, in addition to being expressed in peripheral organs, Sall1 is robustly expressed in progenitor cells of the central nervous system in mice. Both classical- and conditional-knockout mouse studies indicate that the cerebral cortex is particularly sensitive to loss of Sall1. In the absence of Sall1, both the surface area and depth of the cerebral cortex were decreased at embryonic day 18.5 (E18.5). These deficiencies are associated with changes in progenitor cell properties during development. In early cortical progenitor cells, Sall1 promotes proliferative over neurogenic division, whereas, at later developmental stages, Sall1 regulates the production and differentiation of intermediate progenitor cells. Furthermore, Sall1 influences the temporal specification of cortical laminae. These findings present novel insights into the function of Sall1 in the developing mouse cortex and provide avenues for future research into potential neural deficits in individuals with TBS.

Sall3 is a zinc finger containing putative transcription factor and a member of the Sall gene family. Members of the Sall gene family are highly expressed during development. Sall3-deficient mice die in the perinatal period because of dehydration and display alterations in palate formation and cranial nerve formation (Parrish et al. [2004] Mol Cell Biol 24:7102-7112). We examined the role of Sall3 in the development of the olfactory system. We determined that Sall3 is expressed by cells in the olfactory epithelium and olfactory bulb. Sall3 deficiency specifically alters formation of the glomerular layer. The glomerular layer was hypocellular, because of a decrease in the number of interneurons. The lateral ganglionic eminence and rostral migratory stream developed normally in Sall3-deficient animals, which suggests that Sall3 is not required for the initial specification of olfactory bulb interneurons. Fewer GAD65/67-, Pax6-, calretinin-, and calbindin-positive cells were detected in the glomerular layer, accompanied by an increase in cells positive for these markers in the granule cell layer. In addition, a complete absence of tyrosine hydroxylase expression was observed in the olfactory bulb in the absence of Sall3. However, expression of Nurr1, a marker of dopaminergic precursors, was maintained, indicating that dopaminergic precursors were present. Our data suggest that Sall3 is required for the terminal maturation of neurons destined for the glomerular layer. Indexing termsSpalt; 18q deletion syndrome; tyrosine hydroxylase; olfactory bulbThe olfactory bulb (OB) is a laminar structure containing two distinct neuronal populations. Excitatory projection neurons populate the mitral cell layer (MCL), and interneuron populations are located in the glomerular layer (GL) and granule cell layer (GCL), superficial and deep to the MCL respectively. OB neuronal populations are sequentially produced and have distinct origins. Mitral cells are the firstborn OB population (Hinds, 1968). These cells arise in the pallium, and the transcription factor Tbr1 is required for their generation (Bulfone et al., 1998;Moreno et al., 2003;Puelles et al., 2000). OB interneurons arise from an ER81-positive population in the subpallial dorsal lateral ganglionic eminence (LGE) and migrate to the OB via the rostral migratory stream (RMS; Doetsch and Alvarez-Buylla, 1996;Lois and Alvarez-Buylla, 1994;Stenman et al., 2003;Wichterle et al., 1999Wichterle et al., , 2001 Previous studies determined that OB interneurons are continuously generated throughout life (Altman, 1969;Altman and Das, 1966;Doetsch and Alvarez-Buylla, 1996;Hinds, 1968;Lois and Alvarez-Buylla, 1994;Luskin, 1993); however, mechanisms that regulate the generation of this diverse cellular population are not well characterized. OB interneurons begin to express mature interneuron markers as they terminally differentiate and radially migrate in the OB. The OB comprises chemically distinct interneuron populations; at least three subtypes have been identified characterized...

Sall1 is a zinc finger containing transcription factor that is highly expressed during mammalian embryogenesis. In humans, the developmental disorder Townes Brocks Syndrome is associated with mutations in the SALL1 gene. Sall1-deficient animals die at birth due to kidney deficits; however, its function in the nervous system has not been characterized. We examined the role of Sall1 in the developing olfactory system. We demonstrate that Sall1 is expressed by cells in the olfactory epithelium and olfactory bulb (OB). Sall1-deficient OBs are reduced in size and exhibit alterations in neurogenesis and mitral cell production. In addition, the olfactory nerve failed to extend past the ventral-medial region of the OB in Sall1-deficient animals. We observed intrinsic patterns of neurogenesis during olfactory development in control animals. In Sall1-mutant animals, these patterns of neurogenesis were disrupted. These findings suggest a role for Sall1 in regulating neuronal differentiation and maturation in developing neural structures.