Hoxb8 Is Required for Normal Grooming Behavior in Mice

“Functional imaging analysis has led to the description of an OCD circuitusing electrodes implanted into the brainstem have demonstrated that comparable paleocerebellar circuits involving the basal ganglia and components of the neocortex (Graybiel and Rauch, 2000).”

“Curiously, a behavioural syndrome that is characterized by excessive grooming leading to hair removal and lesions has also been attributed to Hoxb8 (Ref”

“In particular, mice lacking the homeobox gene Hoxb8 do not have neuroanatomical defects but have pathological grooming behaviour, in a pattern with similarities to obsessive–compulsive disorder in human”

“Hoxb8 Cell Lineage Gives Rise to Brain Microglia The expression pattern of Hoxb8 in the adult brain is broad (Greer and Capecchi, 2002).”

“…for repetitive or perseverative behaviors (e.g. Eilam et al., 2006; Joel, 2006; Thomas et al., 2009 ), including grooming (Campbell et al., 1999; Greer & Capecchi, 2002; Welch et al., 2007; Shmelkov et al., 2010); anxietyrelated behaviors (e.g. Welch et al., 2007; Shmelkov et al., 2010);…”

“Existing animal models (e.g., Bordnick, Thyer, & Ritchie, 1994; Greer & Capecchi, 2002) and neuroimaging studies (e.g., Stein et al., 2002; Swedo et al., 1991; Vythilingum et al., 2002) suggest an underlying pathogenesis involving a disrupted motor habit system and poor inhibitory control.”

“It also would be of interest for future studies to examine if other animal models of perseverant grooming behavior, such as Hoxb8lox and D1CT mutant mice, also show any exaggerated serial rigidity features in their fixed action patterns similar to those found here [13,51,53-55,57,65].”

“Interestingly, microglial dysfunction has been discovered to contribute to obsessive-compulsive behaviors (Greer and Capecchi 2002), consistent with microglia contributing to the neurobiology of addiction.”

“Ten years ago, mice with a knockout of the HoxB8 gene, a homeobox developmental patterning gene expressed prominently in macrophage-lineage hematopoietic cells, were observed to exhibit excessive grooming behavior; this excessive grooming has been proposed to model OCD symptomatology [103] More recently, HoxB8 mutant…”

“These mouse models include the transgenic D1CT-7 model (over-activation of glutamatergic input to the striatum produced by chronic potentiation of dopamine D1-receptor expressing neurons); the Sapap3/Dlgap3 deletion model (defective corticostriatal glutamatergic transmission) and the Slitrk5 deletion model (increased…”

“Thus, a new class of animal modls related to anxiety/depression and obsessive–compulsive omains, could be developed based on phenomenological, thological, physiological and pharmacogenetic paradigms of nimal OCD-like behaviors [4,63,117,132,173,223,231].”

“Compulsive grooming leading to hair removal and self-inflicted wounds has been identified as a major behavioral phenotype of the Hoxb8 homozygous mutant mouse [21].”

“Markedly elevated grooming is exhibited in three models in particular: the Hoxb8 knockout mouse (34), the Sapap3 knockout mouse (35), and the Slitrk5 knockout mouse (36).”

“For example, homeobox protein B8–deficient (Hoxb8deficient) mice develop extensive grooming behavior with hair loss and skin lesions similar to the human OCD spectrum disorder trichotillomania (79).”

“Compulsive grooming leading to hair removal and selfinflicted wounds has been identified as a major behavioral phenotype of the Hoxb8 homozygous mutant mouse [156] and the Sapap3 KO mouse [104].”

“Spruijt, B.M., Welbergen, P., Brakkee, J. & Gispen, W.H. Behavioral changes in ACTH-(1-24)-induced excessive grooming in aging rats.”

“Considering an ethological model, Greer and Capecchi (2002) reported that mice with a mutation of the hoxb8 neurodevelopmental gene, demonstrated unusual grooming behaviors that included hairpulling.”

“The assessment of induced-grooming followed that of Greer and Capecchi (2002) (also see Supplementary Methods online).”

“Greer and Capecchi (2002) found that mutations on the hoxb8 gene in mice were associated with excessive grooming and hair removal—behaviors that are characteristic of trichotillomania.”

“Grooming behaviour is under the influence of multiple genes, including the Hoxb8 gene, which, when disrupted, leads to excessive self-grooming and allogrooming in mice (Greer & Capecchi, 2002), but other genes that influence this complex behaviour are currently unknown.”

“However, both marble burying and self-grooming assays have also been shown to be sensitive to anxiety [43,44], although there is some controversy as to which behavior each task is most sensitive [25,45].”

“…due to the silencing of the target locus and nearby genes by the methylation of the lacZ bacterial gene as has been previously reported (Thorey et al., 1993; Cohen-Tannoudji et al., 2000; K. D. Economides and M. R. Capecchi 2063The function of Hoxb13 in the prostate Greer and Capecchi, 2002).”

“These include, but are not limited to, the multi-organ malformations that accompany Hoxa3 loss-of-function, the hematologic abnormalities ofHoxb4orHoxa9 loss-of-function, the esophageal dysfunction anddisorganized throat musculature of Hoxc4 loss-of-function and the pathologic excessive grooming behavior ofHoxb8mutant…”

“Hoxb8 mutants as a model of the OC-spectrum disorder, trichotillomania Greer and Capecchi (2002) reported that mice with disruptions of Hoxb8 show excessive grooming compared to control litermates, manifested in longer time spent grooming, more frequent initiation of grooming, the presence of hair…”

“For example, miR196 directly cleaves the mRNA of HOXB8 [47–49], which plays important role in animal development [50–53].”

“In 2002, the Capecchi lab reported that Hoxb8lox mutant mice exhibited compulsive grooming and fur loss with 100% penetrance [27].”

“Excessive lever pressing [22], excessive grooming [23], running [24], and schedule-induced polydipsia [25] have also been described as possible animal models of OCD.”

“In early studies, the authors concluded that, although Hoxb8 is expressed in both the central and peripheral nervous system, the basis of the excessive grooming phenotype was more than likely aberrations in the central rather than peripheral nervous system (Greer and Capecchi 2002).”

“Other constitutive knockout mouse models such as Slitrk5 (Shmelkov et al. 2010), Sapap3 (Welch et al. 2007), Hoxb8 (Greer and Capecchi 2002) and Shank3 (Peca et al. 2011) express compulsive behaviors but primarily in the form of excessive, self-injurious grooming.”

“Hoxb8 overexpression/ Trichotillomania Hoxb8 homozygous mutant mice Excessive grooming (Greer and Capecchi 2002)”

“…not spontaneous , for example resulting from pharmacological or genetic manipulations (Yadin et al., 1991; Ichimaru et al., 1995; Szechtman et al., 1998; Campbell et al., 1999a,b; Joel and Avisar, 2001; Greer and Capecchi, 2002; Chou-Green et al., 2003; Berridge et al., 2005; Tsaltas et al., 2005).”

“Alterations in microglia/myeloid cells have been implicated in pathological grooming, but the underlying mechanism is unclear (28, 29).”

“To address the role of Hoxb8 in the adult brain, Greer and Capecchi [106] created mice homozygous for a loss-of-function allele of Hoxb8.”

“2), which we created because the presence of neo can affect the mouse phenotype by altering the expression of nearby genes (Greer and Capecchi, 2002; Manley et al., 2001).”

“An early study reported that knockout of theHoxb8 gene produces compulsive grooming, progressing to hair removal and ultimately to skin lesions [19].”

“n animals is regarded similar to the symptoms of OCD and ther obsessive–compulsive (OC)-spectrum disorders in humans ncluding trichotillomania [6,7].”

“Candidate genes that seemworth pursuing include hoxB8 (Greer and Capecchi, 2002) and SLITRK1 (abnormalities of which led to trichotillomania in one patient) (Abelson et al., 2005; Zuchner et al., 2006).”

“…idea that microglia may traffic via alternative routes from the fetal yolk sac to the brain gained support from the finding that a proportion of microglia in the brain are derived from fetal yolk sac cells expressing the homeobox 8 (Hoxb8) gene (Chen et al., 2010; Greer & Capecchi, 2002).”

“Manic phenotype (hyperactivity, increased sexual behavior) [20]”

“The assessment of induced-grooming was carried out as previously described (Brimberg et al., 2012; Greer and Capecchi, 2002).”

“Greer JM, Capecchi MR: Hoxb8 is required for normal grooming behavior in mice.”

“For example, microglia are the only brain cells to express Hoxb8, for which mice lacking Hoxb8 exhibit obsessive grooming behavior (Greer and Capecchi 2002).”

“However, since the amount of time devoted to maintenance has a strong genetic basis (Greer and Capecchi, 2002), it is likely that the relative grooming rates of different wild species will be reflected in captive individuals of these same species, making it possible to test the high maintenance…”

“The first class includes D1CT-7 transgenic mice (Campbell et al., 1999a–c; McGrath et al., 1999a,b; Nordstrom and Burton, 2002), Hoxb8 mutant mice (Greer and Capecchi, 2002), 5-HT2c knockout mice (Chou-Green et al., 2003), dopamine transporter knockdown mice (Berridge et al., 2005), aromatase…”

“- HOXB8 Another interesting hypothesis concerning OCD etiology comes from genetic deletion of the Hoxb8 gene in mice, which suggests a link between the immune system and OCD expression [88].”

“2002), the Hoxb8 mutants as a model of the OC-spectrum disorder trichotillomania (Greer and Capecchi 2002), the 5-HT2c receptor knockout mouse as a model of compulsive”

“The orbitofrontal cortex, cingulate cortex and the caudoputamen are implicated in compulsive behavior, which is a common finding in PWS (Dykens et al., 1996; Graybiel and Rauch, 2000; Greer and Capecchi, 2002; Saxena et al., 1998; Warnock and Kestenbaum, 1992; Whitman and Accardo, 1987).”

“Cluster 2 had peak coordinates of [20, 26, 26] and a size of 553 voxels and comprised the bilateral an-”

“Targeted disruption of Hoxb8 gene causes brain specific 6,7 compulsive hair removal behavior closely resembling the OCD spectrum disorder Trichotillomania in humans 21 .”

“55 5-HT2c 5-HT2c receptor KO mouse 5-HT2c receptor KO mice were described by Chou-Green et al to display compulsive-like behavior, comprising more chewing of nonnutritive clay, a distinct pattern of neat chewing of plastic-mesh screen, and reduced habituation of head-dipping activity.”

“The disorganized lamina I neurons might secondarily aberrantly contact their projection targets in the brain, indirectly involving higher brain centers in the phenotype, thus in agreement with the conclusion by Greer and Capecchi (12) in their study of another Hoxb8 mutant allele.”

“Although a specific TTM gene has not been identified in humans, a genetic basis for TTM has been suggested [17,20,21].”

“Genetically engineered mice with Hoxb8 null mutations (Hoxb8) develop severe trichotillomania as their primary phenotype, which may be a primary or complicating part of this disease in C57BL/6 mice.(13) As Hoxb8 is expressed primarily in the brain, RNA was tested from this organ.”

“Hoxb8-knockout mice developed excessive grooming behavior and hair loss [113,114].”

“Mice began to over-groom themselves, and persisted in this behavior even after developing severe facial and body lesions (Greer and Capecchi, 2002).”

“Sapap3 (Welch et al. 2007) and Hoxb8 knockout mice (Greer and Capecchi 2002) exhibit extreme self-grooming that leads to hair loss and skin injuries.”