Joshua Thaler - Academia.edu (original) (raw)

Papers by Joshua Thaler

Nature, 2008

The gut prevents nutrient overload during a meal by promoting satiety and enhancing insulin secre... more The gut prevents nutrient overload during a meal by promoting satiety and enhancing insulin secretion. New findings show that nutrients in the gut also activate a neural circuit that increases insulin sensitivity.

Diabetes, 2010

OBJECTIVE-Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) resu... more OBJECTIVE-Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM.

Diabetes, 2013

Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a r... more Recent evidence suggests that central leptin administration fully normalizes hyperglycemia in a rodent model of uncontrolled insulin-deficient diabetes by reducing hepatic glucose production (HGP) and by increasing glucose uptake. The current studies were undertaken to determine whether brain-derived neurotrophic factor (BDNF) action in the brain lowers blood glucose in uncontrolled insulin-deficient diabetes and to investigate the mechanisms mediating this effect. Adult male rats implanted with cannulas to either the lateral cerebral ventricle or the ventromedial hypothalamic nucleus (VMN) received either vehicle or streptozotocin to induce uncontrolled insulin-deficient diabetes. Three days later, animals received daily intracerebroventricular or intra-VMN injections of either BDNF or its vehicle. We found that repeated daily intracerebroventricular administration of BDNF attenuated diabetic hyperglycemia independent of changes in food intake. Instead, using tracer dilution techniques during a basal clamp, we found that BDNF lowered blood glucose levels by potently suppressing HGP, without affecting tissue glucose uptake, an effect associated with normalization of both plasma glucagon levels and hepatic expression of gluconeogenic genes. Moreover, BDNF microinjection directly into the VMN also lowered fasting blood glucose levels in uncontrolled insulin-deficient diabetes, but this effect was modest compared with intracerebroventricular administration. We conclude that central nervous system BDNF attenuates diabetic hyperglycemia via an insulin-independent mechanism. This action of BDNF likely involves the VMN and is associated with inhibition of glucagon secretion and a decrease in the rate of HGP. Diabetes 62:1512-1518, 2013 G rowing evidence suggests that the brain has a surprisingly potent capacity to normalize blood glucose levels in animals with uncontrolled insulin-deficient diabetes. Even at low doses, leptin infusion directly into the brain completely normalizes diabetic hyperglycemia despite persistent, severe insulin deficiency (1-4). Thus, glucose-lowering in this setting appears to involve mechanisms that are largely independent of either insulin secretion or insulin sensitivity, and identifying neurocircuits that underlie these effects has emerged as an important scientific priority.

Nature communications, Jan 22, 2017

Female mice are less susceptible to the negative metabolic consequences of high-fat diet feeding ... more Female mice are less susceptible to the negative metabolic consequences of high-fat diet feeding than male mice, for reasons that are incompletely understood. Here we identify sex-specific differences in hypothalamic microglial activation via the CX3CL1-CX3CR1 pathway that mediate the resistance of female mice to diet-induced obesity. Female mice fed a high-fat diet maintain CX3CL1-CX3CR1 levels while male mice show reductions in both ligand and receptor expression. Female Cx3cr1 knockout mice develop 'male-like' hypothalamic microglial accumulation and activation, accompanied by a marked increase in their susceptibility to diet-induced obesity. Conversely, increasing brain CX3CL1 levels in male mice through central pharmacological administration or virally mediated hypothalamic overexpression converts them to a 'female-like' metabolic phenotype with reduced microglial activation and body-weight gain. These data implicate sex differences in microglial activation in t...

Diabetes, Jan 10, 2017

Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the h... more Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that CNS action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacologic inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoform Pkc-λ in proopiomelanocortin (POMC) neurons disrupts leptin action, reduces melanocortin content in the paraventricular nucleus, and markedly increases obesity susceptibility, glucose intolerance, and insulin resistance specifically in HFD-fed male mice. These data implicate aPKC as a novel regulator of energy and glucose homeostasis downstream of the leptin-PI3K pathway in POMC neurons.

Diabetologia, 2017

Body weight stability requires homeostatic regulation to balance energy intake and energy expendi... more Body weight stability requires homeostatic regulation to balance energy intake and energy expenditure. Research on this system and how it is affected by obesity has largely focused on the role of hypothalamic neurons as integrators of information about long-term fuel storage, short-term nutrient availability and metabolic demand. Recent studies have uncovered glial cells as additional contributors to energy balance regulation and obesity pathogenesis. Beginning with early work on leptin signalling in astrocytes, this area of research rapidly emerged after the discovery of hypothalamic inflammation and gliosis in obese rodents and humans. Current studies have revealed the involvement of a wide variety of glial cell types in the modulation of neuronal activity, regulation of hormone and nutrient availability, and participation in the physiological regulation of feeding behaviour. In addition, one glial type, microglia, has recently been implicated in susceptibility to diet-induced obe...

Endocrinology, Jul 1, 2013

By activating the Toll-like receptor 4-nuclear factor-kappaB signal transduction pathway, the bac... more By activating the Toll-like receptor 4-nuclear factor-kappaB signal transduction pathway, the bacterial endotoxin lipopolysaccharide (LPS) induces anorexia, weight loss, fever, and other components of the sickness response. By comparison, the hormones leptin and insulin cause anorexia without sickness via a central mechanism involving the phosphatidylinositol-3 kinase signaling pathway. In the current study, we investigated whether a common Toll-like receptor 4 and phosphatidylinositol-3 kinase signaling intermediate, atypical protein kinase Czeta/lambda (aPKC), contributes to changes of energy balance induced by these stimuli. Immunohistochemistry analysis revealed that aPKC is expressed in the arcuate and paraventricular nuclei of the hypothalamus, key sites of leptin, insulin, and LPS action. Although administration of LPS, insulin, and leptin each acutely increased hypothalamic aPKC activity at doses that also reduce food intake, LPS treatment caused over 10-fold greater activation of hypothalamic a PKC signaling than that induced by leptin or insulin. Intracerebroventricular pretreatment with an aPKC inhibitor blocked anorexia induced by LPS but not insulin or leptin. Similarly, LPS-induced hypothalamic inflammation (as judged by induction of proinflammatory cytokine gene expression) and neuronal activation in the paraventricular nucleus (as judged by c-fos induction) were reduced by central aPKC inhibition. Although intracerebroventricular aPKC inhibitor administration also abolished LPS-induced fever, it had no effect on sickness-related hypoactivity or weight loss. We conclude that although hypothalamic aPKC signaling is not required for food intake inhibition by insulin or leptin, it plays a key role in inflammatory anorexia and fever induced by LPS.

American Journal of Physiology Endocrinology and Metabolism, Apr 1, 2010

In peripheral tissues, the link between obesity and insulin resistance involves low-grade inflamm... more In peripheral tissues, the link between obesity and insulin resistance involves low-grade inflammation induced by macrophage activation and proinflammatory cytokine signaling. Since proinflammatory cytokines are also induced in the hypothalamus of animals placed on a high-fat (HF) diet and can inhibit neuronal signal transduction pathways required for normal energy homeostasis, hypothalamic inflammation is hypothesized to contribute to the pathogenesis of diet-induced obesity (DIO). We addressed this hypothesis by perturbing the inflammatory milieu of the hypothalamus in adult male Wistar rats using intracerebroventricular (icv) administration of interleukin-4 (IL-4), a Th2 cytokine that promotes alternative activation (M2) of macrophages and microglia. During HF feeding, icv IL-4 administration increased hypothalamic proinflammatory cytokine gene expression and caused excess weight gain. Intracerebroventricular pretreatment with PS1145, an inhibitor of IKKbeta (a key intracellular mediator of inflammatory signaling), blocked both IL-4 effects, suggesting a causal relationship between IL-4-induced weight gain and hypothalamic inflammation. These observations add to growing evidence linking hypothalamic inflammation to obesity pathogenesis.

Proceedings of the National Academy of Sciences of the United States of America, Jan 21, 2016

Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here,... more Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMN(SF1) neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMN(SF1) neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMN(SF1) fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMN(SF1) neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMN(SF1) neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMN(SF1) neurons and suggest that these neuron...

Current Opinion in Endocrinology & Diabetes and Obesity, 2015

Hypothalamic inflammation and gliosis are recently discovered mechanisms that may contribute to o... more Hypothalamic inflammation and gliosis are recently discovered mechanisms that may contribute to obesity pathogenesis. Current research in this area suggests that investigation of these central nervous system responses may provide opportunities to develop new weight loss treatments. In rodents, hypothalamic inflammation and gliosis occur rapidly with high-fat diet consumption prior to significant weight gain. In addition, sensitivity or resistance to diet-induced obesity in rodents generally correlates with the presence or absence of hypothalamic inflammation and reactive gliosis (brain response to injury). Moreover, functional interventions that increase or decrease inflammation in neurons and glia correspondingly alter diet-associated weight gain. However, some conflicting data have recently emerged that question the contribution of hypothalamic inflammation to obesity pathogenesis. Nevertheless, several studies have detected gliosis and disrupted connectivity in obese humans, highlighting the potential translational importance of this mechanism. There is growing evidence that obesity is associated with brain inflammation in humans, particularly in the hypothalamus where its presence may disrupt body weight control and glucose homeostasis. More work is needed to determine whether this response is common in human obesity and to what extent it can be manipulated for therapeutic benefit.

Nature genetics, 1999

In most mammals the pancreas develops from the foregut endoderm as ventral and dorsal buds. These... more In most mammals the pancreas develops from the foregut endoderm as ventral and dorsal buds. These buds fuse and develop into a complex organ composed of endocrine, exocrine and ductal components. This developmental process depends upon an integrated network of transcription factors. Gene targeting experiments have revealed critical roles for Pdx1, Isl1, Pax4, Pax6 and Nkx2-2 (refs 3,4,5,6,7, 8,9,10). The homeobox gene HLXB9 (encoding HB9) is prominently expressed in adult human pancreas, although its role in pancreas development and function is unknown. To facilitate its study, we isolated the mouse HLXB9 orthologue, Hlxb9. During mouse development, the dorsal and ventral pancreatic buds and mature beta-cells in the islets of Langerhans express Hlxb9. In mice homologous for a null mutation of Hlxb9, the dorsal lobe of the pancreas fails to develop. The remnant Hlxb9-/- pancreas has small islets of Langerhans with reduced numbers of insulin-producing beta-cells. Hlxb9-/- beta-cells e...

Endocrinology, 2014

Gliosis, the activation of astrocyte and microglial cell populations, is a hallmark of central ne... more Gliosis, the activation of astrocyte and microglial cell populations, is a hallmark of central nervous system injury and is detectable using either immunohistochemistry or in vivo magnetic resonance imaging (MRI). Obesity in rodents and humans is associated with gliosis of the arcuate nucleus, a key hypothalamic region for the regulation of energy homeostasis and adiposity, but whether this response is permanent or reversible is unknown. Here we combine terminal immunohistochemistry analysis with serial, noninvasive MRI to characterize the progression and reversibility of hypothalamic gliosis in high-fat diet (HFD)-fed mice. The effects of HFD feeding for 16 weeks to increase body weight and adiposity relative to chow were nearly normalized after the return to chow feeding for an additional 4 weeks in the diet-reversal group. Mice maintained on the HFD for the full 20-week study period experienced continued weight gain associated with the expected increases of astrocyte and microgli...

Abstract—Vascular dysfunction is a major complication of metabolic disorders such as diabetes and... more Abstract—Vascular dysfunction is a major complication of metabolic disorders such as diabetes and obesity. The current studies were undertaken to determine whether inflammatory,responses are activated in the vasculature of mice with diet-induced obesity, and if so, whether Toll-Like Receptor-4 (TLR4), a key mediator of innate immunity, contributes to these responses. Mice lacking TLR4 (TLR4,) and wild-type (WT) controls were fed

Journal of Neuroscience, 2013

Obesity is a growing public health problem. Although convenient, the notion that obesity is simpl... more Obesity is a growing public health problem. Although convenient, the notion that obesity is simply a problem of will power is increasingly antiquated. It is becoming clear that complex interactions of environment, neurohormonal systems, and transgenerational effects directly contribute to obesity. This review highlights data presented at the Society for Neuroscience Annual Meeting in San Diego, California in 2013; and although not meant as an exhaustive review of the area, this reivew will explore seemingly disparate areas of research that, when taken as a whole, illuminate the complex topography of the causes and consequences of obesity. We discuss how disruption of the biological clock, a consequence of modern society, can lead to changes in the brain and periphery that lead to obesity. We explore how obesity can actually cause pathological changes within the hypothalamus of the brain (a key regulator of food intake and metabolic homeostasis). How reward circuitry, particularly the ventral tegmental area, responds to insulin and how these effects modulate feeding and the salience of feeding cues are mechanistically described. We also investigate how nutrition may cross generational boundaries to affect the development and function of offspring, underscoring the long reach of metabolic effects. Finally, the role of the endocannabinoid system is emphasized as a critical node in the transduction of many of these effects. Together, this review should provide perspective into the neural causes and consequences of obesity, and hopefully lead to new areas of interdisciplinary research to tackle this important public health epidemic.

The EMBO Journal, 2005

Ataxin-1 is a neurodegenerative disorder protein whose glutamine-repeat expanded form causes spin... more Ataxin-1 is a neurodegenerative disorder protein whose glutamine-repeat expanded form causes spinocerebellar ataxia type 1 (SCA1) in humans and exerts cytotoxicity in Drosophila and mouse. We report here that the cytotoxicity caused by ataxin-1 is modulated by association with a related protein, Brother of ataxin-1 (Boat). Boat and ataxin-1 share a conserved AXH (ataxin-1 and HMG-box protein 1) domain, which is essential for both proteins' interactions with the transcriptional corepressor SMRT and its Drosophila homolog, SMRTER. The Boat-ataxin-1 interaction is mediated through multiple regions in both proteins, including a newly identified NBA (N-terminal region of Boat and ataxin-1) domain. We investigated the physiological relevance of the Boat-ataxin-1 interaction in Drosophila and discovered that a mutant ataxin-1mediated eye defect is suppressed by ataxin-1's association with Boat. Correspondingly, in transgenic SCA1 mouse, Boat expression is greatly reduced in Purkinje cells, the primary targets of SCA1. Our study thus establishes that Boat is an in vivo binding partner of ataxin-1 whose altered expression in Purkinje cells may contribute to their degeneration in SCA1 animals.

Proceedings of the National Academy of Sciences, 1993

The kinesin heavy chain and the ned (nonclaret disjunctional) gene product of Drosophila are micr... more The kinesin heavy chain and the ned (nonclaret disjunctional) gene product of Drosophila are microtubule-associated motor proteins related by sequence similarity within an -340-aa domain. Despite the sequence similarity, the

Proceedings of the National Academy of Sciences, 2008

In the neurogenic phase of CNS development, the proliferating progenitors are found medially with... more In the neurogenic phase of CNS development, the proliferating progenitors are found medially within the neuroepithelium. The adherens junctions on the apical membrane of proliferating neural progenitors allow for cell-cell adhesion and medial stratification. In contrast, differentiating neuronal precursors delaminate and migrate laterally, establishing the laminar layers. Apical adherens junctions also establish the apical-basal polarity in neural progenitors, which in turn is postulated to lead to asymmetric inheritance of cell fate determinants during neurogenic divisions. The signaling pathways and cellular mechanisms that regulate the assembly and asymmetric localization of adherens junctions in neural progenitors remain elusive. Here we show that atypical PKC/ (aPKC/) localizes at the apical membrane of proliferating neural stem cells, but not postmitotic neuronal precursors, in the developing chicken neural tube. This precise subcellular compartmentalization of the kinase activity provides an instructive signal for apical assembly of adherens junctions in a PI3K, Rac/Cdc42 signaling-dependent pathway. Apical aPKC coordinates neural stem cell proliferation and the overall stratification of cell types within the neural tube.

PLoS ONE, 2012

Despite the suggestion that reduced energy expenditure may be a key contributor to the obesity pa... more Despite the suggestion that reduced energy expenditure may be a key contributor to the obesity pandemic, few studies have tested whether acutely reduced energy expenditure is associated with a compensatory reduction in food intake. The homeostatic mechanisms that control food intake and energy expenditure remain controversial and are thought to act over days to weeks. We evaluated food intake in mice using two models of acutely decreased energy expenditure: 1) increasing ambient temperature to thermoneutrality in mice acclimated to standard laboratory temperature or 2) exercise cessation in mice accustomed to wheel running. Increasing ambient temperature (from 21uC to 28uC) rapidly decreased energy expenditure, demonstrating that thermoregulatory energy expenditure contributes to both light cycle (4061%) and dark cycle energy expenditure (1563%) at normal ambient temperature (21uC). Reducing thermoregulatory energy expenditure acutely decreased food intake primarily during the light cycle (6567%), thus conflicting with the delayed compensation model, but did not alter spontaneous activity. Acute exercise cessation decreased energy expenditure only during the dark cycle (1462% at 21uC; 2164% at 28uC), while food intake was reduced during the dark cycle (0.960.1 g) in mice housed at 28uC, but during the light cycle (0.360.1 g) in mice housed at 21uC. Cumulatively, there was a strong correlation between the change in daily energy expenditure and the change in daily food intake (R 2 = 0.51, p,0.01). We conclude that acutely decreased energy expenditure decreases food intake suggesting that energy intake is regulated by metabolic signals that respond rapidly and accurately to reduced energy expenditure.

Neuron, 2004

structurally related pairs of transcription factors with overlapping expression domains (True and... more structurally related pairs of transcription factors with overlapping expression domains (True and Carroll, 2002). Many such transcription factor pairs have been shown to contribute to progenitor cell diversification (Briscoe and Ericson, 2001). But whether the coordinated expres-Gene Expression Laboratory sion of closely related transcription factor pairs also The Salk Institute participates in the postmitotic diversification of neuronal La Jolla, California 92037 subtypes is less well established. 2 Howard Hughes Medical Institute The spinal cord and hindbrain represent regions of the Department of Biochemistry vertebrate CNS in which some of the steps in neuronal and Molecular Biophysics diversification have been resolved, notably in the con-Columbia University text of motor neuron generation and subtype diversifica-New York, New York 10032 tion (Jessell, 2000; Pfaff and Kintner, 1998). In both the hindbrain and spinal cord, somatic and visceral motor neurons require Shh signaling for their differentiation Summary (Ericson et al., 1997). In the hindbrain, somatic and visceral motor neurons emerge from different ventral pro-LIM homeobox genes have a prominent role in the genitor domains, and thus the distinction in their phenoregulation of neuronal subtype identity and distinguish typic differentiation occurs early in the program of motor motor neuron subclasses in the embryonic spinal cord. neuron generation (Ericson et al., 1997). In the spinal We have investigated the role of Isl-class LIM homeocord, however, somatic and visceral motor neurons are domain proteins in motor neuron diversification using generated from a common set of ventral progenitor cells mouse genetic methods. All spinal motor neuron (Briscoe et al., 1999, 2000; Ericson et al., 1997). Yet, subtypes initially express both Isl1 and Isl2, but Isl2 soon after their generation, postmitotic spinal motor is rapidly downregulated by visceral motor neurons. neurons diversify into distinct functional subclasses Mouse embryos lacking Isl2 function exhibit defects (Jessell, 2000; Pfaff and Kintner, 1998; Shirasaki and in the migration and axonal projections of thoracic Pfaff, 2002), although the mechanisms that control this level motor neurons that appear to reflect a cell-autonprocess remain poorly defined. omous switch from visceral to somatic motor neuron The specification of somatic and visceral spinal motor character. Additional genetic mutations that reduce neuron subtypes represents one of the most fundamenor eliminate both Isl1 and Isl2 activity result in more tal aspects of spinal motor neuron diversification. These pronounced defects in visceral motor neuron generatwo classes of motor neurons settle in different regions tion and erode somatic motor neuron character. Thus, of the spinal cord, innervate different peripheral targets, an early phase of high Isl expression and activity in and receive distinct presynaptic inputs (Levi-Montalcini, newly generated motor neurons permits the diversifi-1950; Lichtman et al., 1980; Markham and Vaughn, cation of visceral and somatic motor neuron subtypes 1991). Somatic motor neurons are generated along the in the developing spinal cord. entire rostrocaudal axis of the spinal cord, settle in the ventral horn, and innervate skeletal muscle targets that Introduction mediate the voluntary control of movement. In contrast, visceral motor neurons of the sympathetic preganglionic The generation of neuronal diversity within the vertemotor column (PGC neurons) arise preferentially at thobrate central nervous system (CNS) depends on the racic levels, settle in the intermediate spinal cord, and specification of discrete sets of progenitor cells with participate in the autonomic control of a diverse array restricted postmitotic neuronal fates (Briscoe et al., of visceral targets (Markham and Vaughn, 1991). The 2000; Desai and McConnell, 2000). Many aspects of divergence of somatic and PGC neuronal identities beneuronal phenotypic diversity are acquired only after comes apparent prior to their migration to distinct setcell cycle exit within sets of neurons that derive from tling positions within the spinal cord (William et al., 2003). an apparently uniform pool of progenitor cells (Jessell, During this period, molecular distinctions in motor neu-2000; Koo and Pfaff, 2002). These postmitotic steps of ron identity, most notably in the profile of expression of neuronal specification appear to control many of the transcription factors, begin to emerge (Jessell, 2000; differential properties of neurons that permit the estab-Shirasaki and Pfaff, 2002; Tsuchida et al., 1994). lishment of appropriate migratory programs and axonal In vertebrates, six pairs of structurally related LIM projections. At a molecular level, specific profiles of homeodomain proteins have been defined, with each transcription factor expression have been shown to diprotein pair typically exhibiting an overlapping profile of rect neuronal diversification (Brunet and Ghysen, 1999; expression (Hobert and Westphal, 2000). Strikingly, four Livesey and Cepko, 2001). One way to enhance the LIM homeodomain protein pairs have been shown to extent of neuronal diversity imposed by transcription function at several sequential steps during motor neuron factors involves the duplication of genes to encode differentiation: in neuronal fate specification, neuronal migration, and axonal pathfinding (Shirasaki and Pfaff, 2002). The LIM homeodomain protein pair Lhx3 and

Neuron, 1999

et al., 1997), Nkx2.2 (Briscoe et al., 1999), and members † Laboratory of Immunoregulation of the... more et al., 1997), Nkx2.2 (Briscoe et al., 1999), and members † Laboratory of Immunoregulation of the Gli family (Hui et al., 1994). Specifically, Nkx2.2 ϩ National Institute of Allergy progenitors appear to produce dorsal exiting MNs (d-MNs) and Infectious Diseases and a class of ventral interneurons (V3), whereas Pax6 ϩ National Institutes of Health progenitors give rise to ventral projecting MNs (v-MNs) Bethesda, Maryland 20892 and a number of distinct interneuron types (V1, V2) (Ericson et al., 1997; Sharma et al., 1998). In an analogous fashion, the dorsal neural tube is patterned by tumor Summary growth factor ␤ (TGF␤) family molecules, including the bone morphogenetic proteins (BMPs) and activin, that Sonic hedgehog (Shh) specifies the identity of both initiate the specification of dorsal neuronal classes (Lee motor neurons (MNs) and interneurons with morphoet al., 1998). gen-like activity. Here, we present evidence that the Many of the transcription factors marking MN and homeodomain factor HB9 is critical for distinguishing interneuron classes have been suspected to control cell MN and interneuron identity in the mouse. Presumpfate specification, yet most are encountered in multiple tive MN progenitors and postmitotic MNs express cell types, including both interneurons and MNs (Tanabe HB9, whereas interneurons never express this factor. and Jessell, 1996; Pfaff and Kintner, 1998). For example, This pattern resembles a composite of the avian hothe LIM-HD factors Lhx3/4, known to promote the v-MN mologs MNR2 and HB9. In mice lacking Hb9, the gecell fate, are present in precursors for both v-MNs and netic profile of MNs is significantly altered, particularly V2 interneurons (Sharma et al., 1998) and can drive exby upregulation of Chx10, a gene normally restricted pression of the V2 gene Chx10 in ectopic contexts (Tanto a class of ventral interneurons. This aberrant gene abe et al., 1998). Thus, it is unclear how an MN utilizes expression is accompanied by topological disorganithese factors to establish its identity while avoiding the zation of motor columns, loss of the phrenic and abduinterneuron characteristics they might confer. More gencens nerves, and intercostal nerve pathfinding defects.