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T. Ott,2, C. Lance-Jones,1 G. Schuetz,3 A. Schwaeger-Nickolenko,3 and A. P. Monaghan1*
Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261,1 Department of Molecular Genetics, Institute for Genetics, 53117 Bonn,2 Division of Molecular Biology of the Cell I, German Cancer Research Center, D-69120 Heidelberg, Germany3
Received 7 July 2003/ Returned for modification 22 August 2003/ Accepted 14 May 2004
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ABSTRACT |
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INTRODUCTION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mutations in at least two of the human Spalt homologues are known to result in autosomal dominant human syndromes. Townes-Brocks syndrome, characterized by imperforate anus, pinna malformations, sensorineural hearing loss, polydactyly, kidney defects, and occasionally mental retardation, is associated with point mutations in SALL1 (7, 16, 25). Mutations in the SALL4 gene have been linked to Okihiro/acro-renal-ocular syndrome, in which patients exhibit forearm malformations and eye movement deficits (1, 28, 29). Although no diseases are yet directly linked to SALL3, this gene is located on chromosome 18 in a region commonly deleted in 18q deletion syndrome. Patients with this deletion exhibit hearing loss, cardiac problems, mental retardation, midfacial hypoplasia, delayed growth, and limb abnormalities (26, 50). No known disorders are associated with mutations in SALL2. It is becoming clear that Sall genes play a crucial role during the development of a number of systems in humans.
The function of Sall proteins in normal cellular and developmental processes is not known. The proteins are predicted to function as transcription factors. The first two zinc fingers of the Drosophila Spalt-related gene product have been shown to possess DNA binding activity, and potent transcriptional repression activity has been demonstrated for the N-terminal regions of human SALL1, murine Sall1, and chicken cSal-1 and cSal-3 proteins (2, 20, 41, 52). Studies of Sall1 have indicated that the transcriptional repression mediated by Spalt transcription factors likely involves histone deacetylase recruitment (20). Although the downstream effects of Spalt expression in these systems remain unclear, recent studies have suggested that Spalt genes may be involved in the regulation of the cell cycle and/or cell adhesion (8, 34, 37).
In an effort to elucidate the role of Sall molecules in vivo, targeted disruptions of these transcription factors were generated in mice. Targeted disruption of Sall1, the murine homologue of human SALL1, supports a role for this gene in kidney development, as these structures fail to form normally in mice that lack Sall1 (42). On the other hand, mice lacking Sall2 fail to demonstrate any abnormal phenotype, a finding which correlates with the fact that no diseases have been associated with its human homologue, SALL2 (49). In order to investigate the function of Sall3, we generated a targeted disruption in the Sall3 gene. The resulting animals survive until birth and die on the first postnatal day. This report describes the phenotype of animals from E9.5 until birth and identifies the structures targeted by loss of the Sall3 gene.
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MATERIALS AND METHODS |
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Mating and staging. Heterozygous Sall3 mutant animals were mated to produce +/+, +/–, and –/– animals. Embryos were collected via cesarian section at different developmental stages ranging from E9.5 to E18.5. Embryonic ages were defined as days postcoitum, and the day of discovery of the vaginal plug was designated E0.5. Embryos were staged by embryonic age and/or physical characteristics. For postnatal ages, the first postnatal day was designated P0.
Behavioral tests. Behavioral tests were performed on newborn pups in order to obtain a general measure of their coordination and response to external stimuli. Pups were collected and kept warm during experiments. They were weighed, and their reaction to pain was tested by a foot pinch. Any squeak elicited in response to the foot pinch was recorded as a positive response. As a general measure of coordination, animals were placed in a lying position on their fore and hind limbs. "Support" was assessed as the ability to support their weight and not fall onto their backs for 3 s. Any animal that did not role onto its back within that 3-s period was scored as +; all others were scored as –. Righting reflexes in these animals were also examined. Animals were rolled onto their backs to elicit a righting response. A positive response was recorded for any animal that lifted its hind limbs and put its forepaws down to right itself. A negative response was recorded for any animal that could not right itself or that lifted its forepaws into the air after a righting response was elicited. Righting responses were limited to these two opposite behaviors.
Histologic analysis. Embryos ranging in age from E9.5 to E18.5 were preserved in Carnoy's fixative and embedded in paraffin. Serial sections of 17 µm were collected for each stage and stained with either hematoxylin-eosin or cresyl violet. Sections were examined and visualized with a Nikon fluorescent microscope and photographed with a Photometrics Cool Snap digital camera and IP Lab software.
In situ hybridization.
Selected 17-µm sections from embryos at E9.5 to E18.5 were processed for in situ hybridization. In situ prehybridization, hybridization, and probe synthesis were carried out as described previously (55). The probes used were Shh (a gift from Andy McMahon), HNF3
(40), HNF3ß (40), Pax6 (a gift from Bob Hill), Sall1 (45), Sall3 (44), and Myf5, Myf6, MyoD, and myogenin (gifts from Marcia Ontell). Probes were hydrolyzed to 200-bp fragments, dissolved at 60 ng/ml in hybridization buffer, and hybridized overnight at 63°C (55). Slides were dipped in Kodak NTB2 emulsion diluted 1:1 with water, exposed at 4°C for 5 to 10 days, and developed in Kodak D19 and Kodakfix at 15°C for 4 min. Sections then were counterstained with hematoxylin-eosin or cresyl violet.
Whole-mount neurofilament staining. E10.5 embryos were collected in phosphate-buffered saline (PBS), extraembryonic membranes were dissected away, and a small piece of tail or foot was retained for PCR genotyping. Embryos then were fixed overnight at 4°C in Dent's fixative (methanol-dimethyl sulfoxide [4:1]). Whole-mount neurofilament staining was performed as previously described (54). Mouse anti-neurofilament 160 primary antibody (Sigma clone NN18) was diluted 1/40 in PBS-2% Carnation milk powder-0.1% Triton X-100. Sall3–/– embryos were matched with a +/+ littermate. Occasionally, mutant embryos outnumbered +/+ littermates. In these instances, a +/– littermate match was selected (n = 26; 26 –/– versus 20 +/+ and 6 +/–). Excluding +/– animals and their –/– littermate matches from this analysis had no consistent effect on the outcome.
ß-Galactosidase staining. Newborn animals were sacrificed and decapitated. The skull was opened and immersion fixed in 4% paraformaldehyde-PBS at 4°C for 1 h. Newborn heads were rinsed in cold PBS, then immersed in PBS containing 4 mM potassium ferricyanide, 4 mM potassium ferrocyanide, 0.01% sodium deoxycholate, 0.02% NP-40, 2 mM magnesium chloride, and 1 mg of 5-bromo-4-chloro-3-indolyl-ß-D-galactopyranoside (X-Gal)/ml, and gently agitated at 37°C overnight.
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RESULTS |
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Sall3 is required for perinatal survival. Heterozygous animals were fertile, indistinguishable from wild-type animals, and were intercrossed to produce homozygous progeny. Sall3–/– animals were produced at the expected Mendelian ratio and were alive at the time of birth (Table 1) but did not survive. These animals were of normal weight and length and were usually indistinguishable from littermates (Table 1 and data not shown). All but one Sall3 mutant animal died or was cannibalized within 12 h after birth.
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We performed additional behavioral tests on mutant animals to assess the basic functionality of sensory and motor systems in Sall3–/– animals at birth. All mutant animals responded to painful stimuli (foot pinch); however, more than half of the mutants assessed were less capable of supporting their weight than their littermates (Table 1). A few (3 of 11; Table 1) Sall3 mutant animals also had altered righting reflexes (Table 1). These mutant pups moved their limbs in directions opposite those of wild-type and heterozygous animals when a righting response was elicited. These findings indicate that gross motor and sensory systems are intact but that subtle abnormalities may exist in motor coordination in Sall3–/– animals.
The morphology of the oral cavity is abnormal in Sall3–/– animals. Ott et al. (44, 45) previously reported the patterns of expression of Sall1 and Sall3 in developing craniofacial regions in early development (E7.5 to E12.5). These studies indicated that transcripts for Sall1 and Sall3 are transiently found in tissues that give rise to structures of the palate and tongue and in regions of the central nervous system that innervate these structures (44, 45). In light of these findings and the observed suckling deficits in mutant animals, we assessed the normal distribution of Sall3 transcripts in developing craniofacial regions at later developmental stages (E14.5 until birth). From E14.5 on, Sall3 expression is up-regulated in the developing palate and tongue (Fig. 2A to D). Sall3 is found in a prominent band parallel to the dorsal surface of the tongue, with moderate expression in several other developing muscle groups of the tongue (Fig. 2D). Sall3 is also strongly expressed in the frontonasal process (Fig. 2D). In the palate, it is expressed in the mesenchyme of the rugae. Anteriorly, expression is found at the point of fusion of the primary and secondary palates (Fig. 2C); posteriorly, expression is found in areas surrounding the epiglottis and the opening of the nasopharynx and oropharynx (Fig. 2C). At P0, Sall3 is highly expressed in the rugae and in the primary and secondary palates. Sall3 transcripts are also found in developing cranial ganglia from E14.5 until birth (Fig. 2A, B, and E). In particular, the glossopharyngeal (IX), trigeminal (V), and vestibulocochlear (VIII) ganglia express robust levels of Sall3 at E16.5 (Fig. 2E). The related family member Sall1 is expressed in overlapping regions in the developing brain and palate at early developmental stages (45). At E16.5, Sall1 is also highly expressed in the glossopharyngeal (IX), trigeminal (V), and vestibulocochlear (VIII) ganglia (Fig. 2F). Differences were not observed in the expression of Sall3 transcripts detected by in situ hybridization and ß-galactosidase staining in heterozygous and mutant animals, indicating that Sall3 does not regulate its own expression in developing craniofacial regions.
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Deficits in the tongue could also contribute to the abnormal feeding behavior observed in Sall3–/– animals at birth. We first examined the structure and the musculature of the tongues of Sall3+/+ and Sall3–/– animals in whole mounts and in serial coronal and sagittal sections stained with hematoxylin-eosin. At P0, multinucleate striated muscle of the tongue was organized into the typical intrinsic and extrinsic muscle groups in both wild-type and mutant littermates (n = 5). Taste buds were similar in size and number on the superior surface of the tongue in both wild-type and mutant animals. Measurements of the width of tongues revealed that the anterior portion of mutant tongues was, on average, 8% wider than that of wild-type littermate tongues (n = 5) (P < 0.05). To determine whether the deficits observed in the tongues at birth had a developmental origin, histological examination of the development of wild-type and mutant tongues and the surrounding mandible, maxilla, and dentition was performed with serial coronal and sagittal sections from E10 to E16.5. Differences in the size or organization of the tongues were not observed at these stages. Furthermore, the expression of the myogenic regulatory genes MRF-4, MRF-5, myogenin, and Myo-D was analyzed in Sall3–/– animals by in situ hybridization at E14.5, near the peak of their expression (57). All regulatory factors investigated were expressed at E14.5 in mutant tongues at levels and locations indistinguishable from those observed in wild-type littermate tongues (data not shown).
Sall3 is expressed not only at late developmental stages (E14 on) in oral structures but also earlier in the tissues and cells that give rise to these elements. The observed abnormalities in tissues surrounding the oral cavity could therefore reflect an earlier abnormality in patterning. To begin to answer this question, we examined the expression of a number of markers that are expressed in either the epithelium or the mesenchyme by in situ hybridization. Sonic hedgehog (Shh) (Fig. 4A to D), HNF3 (Fig. 4E to H), and Pax1 (data not shown) were used as markers of the epithelium of the first branchial arch, tongue, and palate. Msx2 was used as a mesenchyme marker for the first branchial arch and facial mesenchyme (data not shown). From E9.5 to E12.5, no differences in the patterns of expression of these markers between wild-type and mutant animals were observed.
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In the majority of control embryos (77%), a clearly defined glossopharyngeal nerve (IX) arose from the lateral surface of the hindbrain, just rostral to the vagal (X) and spinal (XI) accessory nerves (Table 2 and Fig. 5A). In a minority of wild-type embryos, either the proximal glossopharyngeal nerve was indivisible from the vagal or spinal accessory nerves or small connections existed between the two trunks (Fig. 5C). The frequency of these fusions or connections in Sall3–/– animals was doubled (46 versus 23%; Table 2) and was more severe than that in wild-type animals (Fig. 5C, D, and E). In addition, in 8% of mutant embryos (2 of 26), the inferior glossopharyngeal ganglion lacked a connection to the hindbrain (Fig. 5F and Table 2). This type of abnormality was never observed in control embryos. Abnormalities in the glossopharyngeal nerve, which mediates visceral sensations of the posterior oral cavity important in swallowing, also may have been partially responsible for the feeding deficits exhibited by Sall3–/– animals.
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Finally, dorsal root-like ganglia persisted at the anterior cervical levels in 15% of mutant embryos, while these structures were observed in only 8% of control embryos (Table 2). Prior studies suggested that such transient ganglia can occur normally in vertebrates (33); however, these abnormalities were observed more often in Sall3–/– animals. In half of the affected mutant animals, these supernumerary ganglia were also bilateral, while in the control animals, these structures were always unilateral (data not shown).
The glossopharyngeal and hypoglossal nerves innervate sensory and motor aspects of the tongue, respectively. To determine whether the abnormalities observed between E10.5 and E11.5 in these nerves led to an altered pattern of innervation of the tongue, serial sagittal sections of the tongue stained with anti-neurofilament 160 antibody were examined from E16 to birth (n = 2). Tongues of wild-type and mutant animals were both densely innervated. No gross abnormalities were observed in the innervation patterns of the tongues of Sall3 mutant animals.
To determine whether the hypoglossal nucleus in the brain stem was normal in Sall3 mutant animals, we examined the expression of neurofilaments in serial coronal sections of the brain stem at P0. Neurons in the nucleus appeared to be similar in size and location, and their axons could be visualized projecting ventrolaterally from the nucleus to the ventral surface of the hindbrain and into the periphery (Fig. 6A to D).
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(Fig. 7B and C), Shh (data not shown), and HNF3ß (data not shown) as markers of the notochord and floor plate and Pax6 as a regional spinal cord marker by in situ hybridization from E10.5 to E12.5 (Fig. 7E and F). No differences in the expression domains for these markers were observed (n = 3). Furthermore, alizarin red and alcian blue studies verified that skeletal and cartilaginous elements of the ribs, vertebrae, and limbs had developed normally (n = 6).
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Sall3 is required for the terminal development of several oral structures. Sall3 is expressed in the mesenchyme of the branchial arches early in development (from E8.5 on). It is subsequently down-regulated in oral structures derived from arch tissue until E13.5. At this time, intense expression of Sall3 appears within the palate at sites of midline and anterior fusion, in rugae, and in tongue musculature. At birth, expression is evident in the palate, epiglottis, nasopharynx, and oropharynx. The dynamic nature of these expression patterns suggests that Sall3 plays multiple roles in craniofacial development.
In Sall3 mutant animals, abnormalities in craniofacial structures were evident at mid-gestation and at birth. From E16 to P0, the palates of Sall3–/– animals terminate prematurely, and the velum was reduced or absent. Additionally, the epiglottis of mutant animals was reduced in size, and the tongue was widened anteriorly. These abnormalities would lead to an inability of the palate and pharynx to close and allow air to escape during swallowing and speech. Closure of the palate and pharynx during feeding is necessary to produce the appropriate suction to extract milk from the mother and subsequently to separate air from food to prevent aspiration and allow normal feeding and breathing. Interestingly, in addition to poor sucking or swallowing reflexes, humans with velopharyngeal insufficiency, characterized by a failure of the palate and pharynx to close, also exhibit hypernasality as air leaks from the nose during speech. Sall3–/– animals may also have abnormal vocalizations as a consequence of these palate deficiencies.
In spite of the early and widespread pattern of expression of Sall3 in branchial mesenchyme, the majority of palatal development and fusion occurs normally. In the absence of Sall3, alternate Spalt family members may compensate during early development in mutant animals. Sall1 is a likely candidate as it is also found in the 1st branchial arch and in head mesenchyme from E8 until E13.5 (45). At later stages (E14 on), Sall1 is not robustly expressed in the palate (M. Parrish and A. P. Monaghan, unpublished data) and is therefore unlikely to compensate for Sall3. Two additional Sall genes, Sall2 and Sall4, have been identified, and it will be interesting to define their expression patterns in the developing craniofacial regions.
Spalt homologues have been shown to be downstream targets of sonic hedgehog (Shh) signaling in vertebrates (30, 51). Humans and mice with mutations in Sall1 (SALL1; Townes-Brocks disorder) exhibit renal, ear, limb, anal, and cardiac abnormalities (21, 25, 42, 53). Patients with 18q deletion syndrome, that encompasses the SALL3 locus among other genes (26) also exhibit ear, limb, and cardiac as well as face and palatal deficiencies (56). Many of these abnormalities are also found in patients with alterations in Shh signaling. For example, patients with mutations in Gli3 (Pallister-Hall [PH] syndrome), a downstream target of Shh, exhibit, renal, ear, limb, anal, and cardiac abnormalities. Most strikingly, patients with PH syndrome can have laryngeal cleft and hypoplasia or absence of the epiglottis, similar to our findings for Sall3-deficient animals (4, 19, 38). Also, the VACTERL association that has been hypothesized to be a consequence of altered Shh signaling, includes tracheal-esophageal fistula, renal, limb, anal, and cardiac deficiencies (9, 22, 23, 35, 36, 47). Our observations on the Sall3 phenotype strengthens the link between Sall and Shh signaling and raises the possibility that reduced Sall expression or signaling could contribute to the phenotypes observed in syndromes such as PH syndrome.
Sall3 is important for cranial nerve development. Several minor cranial nerve abnormalities were observed in Sall3 mutant animals. Although occasionally present in wild-type animals, the deficits observed were more frequent and of greater severity in Sall3–/– animals. The glossopharyngeal nerve (cranial nerve IX) was most consistently affected. This nerve mediates visceral sensory input from the posterior aspect of the tongue and palate in addition to other functions important in swallowing. Deficits in the function of this nerve would likely compound feeding difficulties resulting from the abnormal structure of the tongue, palate and epiglottis and contribute to the perinatal lethality observed in these animals. The hypoglossal nerve (XII) that innervates the genioglossal, hypoglossal, styloglossal and intrinsic muscles of the tongue was also variably altered in the absence of Sall3. Subtle alterations in the innervation pattern could lead to uncoordinated movements of the tongue during mastication and swallowing. The absence of overt abnormalities in the innervation pattern of the tongue at birth could be misleading. These subtle abnormalities could be difficult to detect due to the variable and unilateral nature of the defects observed during early embryonic development. It is therefore possible that more quantitative methods could reveal subtle abnormalities at birth. In light of this possibility, it is interesting that some mutants show an anterior enlargement of the tip of the tongue. It is also possible that the cranial nerve alterations observed at E10.5 are compensated for at later developmental stages. It is interesting that the deficits in the glossopharyngeal nerve described here are identical to those seen in animals in which mCoup-TFI has been disrupted (46). Similarities between Sall3 and mCoup-TFI in their function or the downstream effectors they impinge upon have yet to be fully described. It remains unclear if these deficits are a direct result of altered expression of Sall3 in the hindbrain or a secondary effect of alterations in branchial arch development resulting from the absence of Sall3 in these structures.
Role of Sall3 in spinal cord development. Although Sall3 mutant animals responded to painful stimuli and demonstrated functionality of a number of sensory and motor systems, they were less capable of supporting their weight than their littermates and occasionally exhibited altered righting reflexes. General structure and development of the spinal cord, however, appeared normal. It is possible that defects exist in spinal cords of Sall3 mutant animals and would be revealed by electrophysiological or ultrastructural analysis. These behaviors, however, might be more simply explained by alterations in balance information conveyed by the inner ear or possibly attributed to the effects of dehydration. Sall3 is highly expressed in the inner ear during development and, although we observed no gross perturbations in this structure, changes in physiological function were not explored in this study.
The phenotype of Sall3 mutant animals is surprisingly mild in comparison to its expression pattern. Sall3 is expressed from E7 throughout the rest of development and also in the adult (45; Parrish and Monaghan, unpublished). The Sall1 and Sall3 gene products have similar structures, and their expression patterns differ only slightly in timing and location. Further studies will determine whether other Sall family members can compensate for Sall3 during development. If functional compensation can occur between members of the Spalt transcription factor family, compound mutations will be necessary to fully explore the role of Spalt genes in murine development.
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ACKNOWLEDGMENTS |
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This study was supported by NIMH grant no. 5RO1MH060774-03, MOD Basil O'Connor grant no. S-FY98-756, and NIH grant no. T32 MH18273.
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FOOTNOTES |
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M.P. and T.O. contributed equally to this work.
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